| 1 | Neuropsychopharmacology 2000 Aug 23: 216-9 |
|---|---|
| PMID | 10882848 |
| Title | Abnormal levels of cAMP-dependent protein kinase regulatory subunits in platelets from schizophrenic patients. |
| Abstract | Abnormalities in the CAMP-dependent protein kinase (PKA), a central component of CAMP signaling, have been reported in several psychiatric disorders. Previous studies showed CAMP signaling alterations in schizophrenic patients but less is known about the involvement of PKA in such disorder. Therefore, we investigated the PKA subunits by Western blot analysis in platelets from 12 patients with schizophrenia and 13 controls. The results showed that the immunolabeling of the PKA regulatory subunits type I (RI) and type II (RII) was significantly reduced in patients compared with controls whereas no differences were observed in the catalytic (C) subunit of the enzyme. These preliminary data suggest that schizophrenic patients have altered PKA levels, thus supporting that dysfunctions in the components of CAMP signaling may contribute to the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 2 | Neuropsychopharmacology 2000 Aug 23: 216-9 |
| PMID | 10882848 |
| Title | Abnormal levels of cAMP-dependent protein kinase regulatory subunits in platelets from schizophrenic patients. |
| Abstract | Abnormalities in the CAMP-dependent protein kinase (PKA), a central component of CAMP signaling, have been reported in several psychiatric disorders. Previous studies showed CAMP signaling alterations in schizophrenic patients but less is known about the involvement of PKA in such disorder. Therefore, we investigated the PKA subunits by Western blot analysis in platelets from 12 patients with schizophrenia and 13 controls. The results showed that the immunolabeling of the PKA regulatory subunits type I (RI) and type II (RII) was significantly reduced in patients compared with controls whereas no differences were observed in the catalytic (C) subunit of the enzyme. These preliminary data suggest that schizophrenic patients have altered PKA levels, thus supporting that dysfunctions in the components of CAMP signaling may contribute to the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 3 | J Neural Transm (Vienna) 2000 -1 107: 501-9 |
| PMID | 11215760 |
| Title | Abnormal protein phosphorylation in post-mortem brain tissue from bipolar patients. |
| Abstract | Abnormal phosphorylation has been proposed to be involved in the pathogenesis of affective disorders. The present study investigated basal and CAMP-stimulated endogenous protein phosphorylation in human post-mortem brain tissue from bipolar and schizophrenic patients. Furthermore, basal kinase activity and stimulated protein kinase A activity were measured. The frontal and occipital cortex were analysed. Using [gamma-32P]ATP as phosphate donor, basal and CAMP-stimulated phosphorylation of endogenous proteins was measured in the absence or presence of 8-Br-CAMP, respectively. The proteins were separated on SDS-gels and the radioactivity in the individual bands was measured. We observed a significant reduction of 32P incorporation in three protein substrates (15, 16 and 21 kD) in frontal cortex of bipolar patients. However, there were no differences in the PKA activity between any of the groups. The present study demonstrates abnormal phosphorylation of specific proteins in brain tissue obtained from bipolar patients in comparison to schizophrenics and controls. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 4 | J Neural Transm (Vienna) 2000 -1 107: 501-9 |
| PMID | 11215760 |
| Title | Abnormal protein phosphorylation in post-mortem brain tissue from bipolar patients. |
| Abstract | Abnormal phosphorylation has been proposed to be involved in the pathogenesis of affective disorders. The present study investigated basal and CAMP-stimulated endogenous protein phosphorylation in human post-mortem brain tissue from bipolar and schizophrenic patients. Furthermore, basal kinase activity and stimulated protein kinase A activity were measured. The frontal and occipital cortex were analysed. Using [gamma-32P]ATP as phosphate donor, basal and CAMP-stimulated phosphorylation of endogenous proteins was measured in the absence or presence of 8-Br-CAMP, respectively. The proteins were separated on SDS-gels and the radioactivity in the individual bands was measured. We observed a significant reduction of 32P incorporation in three protein substrates (15, 16 and 21 kD) in frontal cortex of bipolar patients. However, there were no differences in the PKA activity between any of the groups. The present study demonstrates abnormal phosphorylation of specific proteins in brain tissue obtained from bipolar patients in comparison to schizophrenics and controls. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 5 | Naunyn Schmiedebergs Arch. Pharmacol. 2000 Nov 362: 375-81 |
| PMID | 11111831 |
| Title | Functions of neuronal adenosine receptors. |
| Abstract | Endogenous adenosine in nervous tissue, a central link between energy metabolism and neuronal activity, varies according to behavioral state and (patho)physiological conditions, it may be the major sleep propensity substance. The functional consequences of activation of the four known adenosine receptors, A1, A2A, A2B and A3, are considered here. The mechanisms and electrophysiological actions, mainly those of the A1-receptor, have been extensively studied using in vitro brain-slice preparations. A1-receptor activation inhibits many neurons postsynaptically by inducing or modulating ionic currents and presynaptically by reducing transmitter release. A1-receptors are almost ubiquitous in the brain and affect various K+ (Ileak, IAHP), mixed cationic (Ih), or Ca2+ currents, through activation of Gi/o-proteins (coupled to ion channels, adenylyl cyclase or phospholipases). A2A-receptors are much more localized, their functional role in the striatum is only just emerging. A2B- and A3-receptors may be affected in pathophysiological events, their function is not yet clear. The CAMP-PKA signal cascade plays a central role in the regulation of both neural activity and energy metabolism. Under conditions of increased demand and decreased availability of energy (such as hypoxia, hypoglycemia and/or excessive neuronal activity), adenosine provides a powerful protective feedback mechanism. Interaction with adenosine metabolism is a promising target for therapeutic intervention in neurological and psychiatric diseases such as epilepsy, sleep, movement (parkinsonism or Huntington's disease) or psychiatric disorders (Alzheimer's disease, depression, schizophrenia or addiction). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 6 | Psychopharmacology (Berl.) 2000 Jul 150: 383-90 |
| PMID | 10958079 |
| Title | Effects of recent and reference antipsychotic agents at human dopamine D2 and D3 receptor signaling in Chinese hamster ovary cells. |
| Abstract | Central dopamine D2 receptor blockade is an essential property of antipsychotic agents in the treatment of schizophrenia. However, for certain of the newer antipsychotics (e.g., sertindole), the in vitro D2 receptor binding affinity does not correlate with in vivo central dopamine antagonism. This study aimed to investigate the effect and potency of haloperidol, pipamperone, clozapine, risperidone, sertindole, zotepine, olanzapine, and quetiapine on signaling pathways of human dopamine D2S and D3 receptors expressed in Chinese hamster ovary cells and to relate this to their dopamine antagonist potency in vivo. Chinese hamster ovary cells, stably expressing high levels of hD2S and hD3 receptors were cultured: dopamine-stimulated [35S]-GTPgammaS binding was investigated in cell membrane preparations, and forskolin-induced CAMP formation was measured in intact cells. The antipsychotic agents inhibited dopamine-stimulated [35S]-GTPgammaS binding mediated by hD2S and hD3 receptors with potencies equal to their receptor binding affinities. The antipsychotics reversed dopamine inhibition of CAMP formation (equally well detectable with both hD2S and hD3 receptors) dose dependently at both receptors. Partial agonist effects were not observed with any of the antipsychotics. Antagonistic potencies of haloperidol, risperidone, and pipamperone in the CAMP test were equal to their receptor binding affinities. Sertindole and olanzapine were more than ten times less potent dopamine antagonists in the intact cell assay than in the assay using cell membranes; the other compounds showed less marked potency differences. Olanzapine and sertindole were less efficacious dopamine antagonists in intact cell assays, possibly due to avid uptake in cells. For sertindole, the weak hD2S receptor antagonism in intact cells corresponded to a weak in vivo central dopamine antagonism assessed in rats. However, for olanzapine, hD2S receptor binding affinity correlated better with its in vivo dopamine antagonist potency. Such discrepancies may be further explained by relative differences of the compounds in penetrating into the brain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 7 | Arch. Gen. Psychiatry 2000 Jul 57: 685-91 |
| PMID | 10891039 |
| Title | Increased levels of transcription factors Elk-1, cyclic adenosine monophosphate response element-binding protein, and activating transcription factor 2 in the cerebellar vermis of schizophrenic patients. |
| Abstract | We investigated the levels of transcription factors associated with activation of the mitogen-activated protein (MAP) kinase pathway in schizophrenics using postmortem brain samples. These studies were done to determine whether our previous findings of abnormal levels of the MAP kinases in the cerebellar vermis were linked to additional downstream targets of this signal transduction pathway. We measured the protein levels of 3 transcription factors in nuclear fractions of postmortem samples from cerebellar vermis of 10 patients with schizophrenia and 13 control subjects: Elk-1, cyclic adenosine monophosphate (CAMP) response element binding protein (CREB), and activating transcription factor 2 (ATF-2). Studies in rats examined the postmortem stability and effect of haloperidol and risperidone on levels of Elk-1, CAMP, and ATF-2 proteins. We found a significant increase in the protein levels of Elk-1 (mean+SD, 4489+/-659 vs 2915+/-583 arbitrary densitometric units [P<.001]), CREB (mean +/- SD, 2149 1061 vs 904+/-711 arbitrary densitometric units [P=.003]) and ATF-2 (mean+/-SD, 1421 854 vs 512+/-394 arbitrary densitometric units [P=.003]) in the cerebellar vermis of schizophrenic subjects. Complementary studies in rats indicate that these findings can not be attributed to subacute treatment with antipsychotic medications. Taken together with the alterations of MAP kinases previously reported, and the findings of elevations of downstream transcription targets, we suggest that the MAP kinase signal transduction pathway contributes to the cerebellar abnormalities in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 8 | Arch. Gen. Psychiatry 2000 Jul 57: 685-91 |
| PMID | 10891039 |
| Title | Increased levels of transcription factors Elk-1, cyclic adenosine monophosphate response element-binding protein, and activating transcription factor 2 in the cerebellar vermis of schizophrenic patients. |
| Abstract | We investigated the levels of transcription factors associated with activation of the mitogen-activated protein (MAP) kinase pathway in schizophrenics using postmortem brain samples. These studies were done to determine whether our previous findings of abnormal levels of the MAP kinases in the cerebellar vermis were linked to additional downstream targets of this signal transduction pathway. We measured the protein levels of 3 transcription factors in nuclear fractions of postmortem samples from cerebellar vermis of 10 patients with schizophrenia and 13 control subjects: Elk-1, cyclic adenosine monophosphate (CAMP) response element binding protein (CREB), and activating transcription factor 2 (ATF-2). Studies in rats examined the postmortem stability and effect of haloperidol and risperidone on levels of Elk-1, CAMP, and ATF-2 proteins. We found a significant increase in the protein levels of Elk-1 (mean+SD, 4489+/-659 vs 2915+/-583 arbitrary densitometric units [P<.001]), CREB (mean +/- SD, 2149 1061 vs 904+/-711 arbitrary densitometric units [P=.003]) and ATF-2 (mean+/-SD, 1421 854 vs 512+/-394 arbitrary densitometric units [P=.003]) in the cerebellar vermis of schizophrenic subjects. Complementary studies in rats indicate that these findings can not be attributed to subacute treatment with antipsychotic medications. Taken together with the alterations of MAP kinases previously reported, and the findings of elevations of downstream transcription targets, we suggest that the MAP kinase signal transduction pathway contributes to the cerebellar abnormalities in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 9 | Arch. Gen. Psychiatry 2000 Jul 57: 685-91 |
| PMID | 10891039 |
| Title | Increased levels of transcription factors Elk-1, cyclic adenosine monophosphate response element-binding protein, and activating transcription factor 2 in the cerebellar vermis of schizophrenic patients. |
| Abstract | We investigated the levels of transcription factors associated with activation of the mitogen-activated protein (MAP) kinase pathway in schizophrenics using postmortem brain samples. These studies were done to determine whether our previous findings of abnormal levels of the MAP kinases in the cerebellar vermis were linked to additional downstream targets of this signal transduction pathway. We measured the protein levels of 3 transcription factors in nuclear fractions of postmortem samples from cerebellar vermis of 10 patients with schizophrenia and 13 control subjects: Elk-1, cyclic adenosine monophosphate (CAMP) response element binding protein (CREB), and activating transcription factor 2 (ATF-2). Studies in rats examined the postmortem stability and effect of haloperidol and risperidone on levels of Elk-1, CAMP, and ATF-2 proteins. We found a significant increase in the protein levels of Elk-1 (mean+SD, 4489+/-659 vs 2915+/-583 arbitrary densitometric units [P<.001]), CREB (mean +/- SD, 2149 1061 vs 904+/-711 arbitrary densitometric units [P=.003]) and ATF-2 (mean+/-SD, 1421 854 vs 512+/-394 arbitrary densitometric units [P=.003]) in the cerebellar vermis of schizophrenic subjects. Complementary studies in rats indicate that these findings can not be attributed to subacute treatment with antipsychotic medications. Taken together with the alterations of MAP kinases previously reported, and the findings of elevations of downstream transcription targets, we suggest that the MAP kinase signal transduction pathway contributes to the cerebellar abnormalities in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 10 | J Neural Transm (Vienna) 2001 -1 108: 849-54 |
| PMID | 11515750 |
| Title | Association analysis of the pituitary adenyl cyclase activating peptide gene (PACAP) on chromosome 18p11 with schizophrenia and bipolar disorders. |
| Abstract | In neurons, pituitary adenyl cyclase activating peptide (PACAP) stimulates signaling cascades, involving CAMP and calcium. PACAP appears to play a role in up-regulation of tyrosine hydroxylase and dopamine beta-hydroxylase via protein kinase C and/or protein kinase A. Furthermore, the PACAP gene (ADCYAP1) is located in chromosome 18p11, where linkage of bipolar disorders and schizophrenia has been reported. In this study, we scanned the coding region of the PACAP gene for mutations in 24 Japanese patients with schizophrenia and 24 Japanese patients with bipolar disorders. No variant in the coding region was found. One polymorphism, INV3-37A/T, in the third intron was detected. Case-control comparisons revealed no significant association between this polymorphism and schizophrenia or bipolar disorders. This study did not provide evidence for the contribution of the PACAP gene to the etiology of schizophrenia or bipolar disorders in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 11 | Biol. Psychiatry 2001 Aug 50: 260-5 |
| PMID | 11522260 |
| Title | Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. |
| Abstract | The CAMP signaling pathway, and its downstream neurotrophic factor BDNF, are major targets of antidepressant medications. Abnormalities in this pathway have previously been reported in postmortem brain of subjects with mood disorders. This study was designed to test whether the diagnosis of a mood disorder, or treatment with an antidepressant or mood stabilizer was associated with changes in hippoCAMPal BDNF in postmortem brain. Frozen postmortem anterior hippoCAMPus sections were obtained from the Stanley Foundation Neuropathology Consortium. Tissue from subjects with major depression, bipolar disorder, schizophrenia and nonpsychiatric control subjects were stained for BDNF using immunohistochemistry. Increased BDNF expression was found in dentate gyrus, hilus and supragranular regions in subjects treated with antidepressant medications at the time of death, compared with antidepressant-untreated subjects. Furthermore, there was a trend toward increased BDNF expression in hilar and supragranular regions in depressed subjects treated with antidepressants, compared with the subjects not on these medications at the time of death. These findings are consistent with recent studies measuring CREB levels in this same subject sample, and support current animal and cellular models of antidepressant function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 12 | J Addict Dis 2001 -1 20: 33-42 |
| PMID | 11681591 |
| Title | Signal transduction mechanisms and behavioral sensitization to stimulant drugs: an overview of cAMP and PLA2. |
| Abstract | Behavioral sensitization refers to the progressive increase of behavioral responses to psychomotor stimulants, which provides a model for the intensification of drug craving and relapse alleged to underlie addiction in humans. Mechanisms related to sensitization may also contribute to schizophrenia and bipolar disorder. While the phenomenon has been observed for years, only recently have molecular or intracellular mechanisms associated with behavioral sensitization been studied. An overview of CAMP and PLA2 (intracellular, signal transduction mechanisms) relevant to behavioral sensitization will be presented. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 13 | Eur Neuropsychopharmacol 2001 Jun 11: 221-5 |
| PMID | 11418282 |
| Title | The cAMP-dependent protein kinase substrate Rap1 in platelets from patients with obsessive compulsive disorder or schizophrenia. |
| Abstract | Previous studies have reported that the CAMP-dependent protein kinase and one of its substrates, namely Rap1, are altered in patients with affective disorders. Abnormalities in the CAMP-dependent protein kinase have also been reported in platelets of patients with obsessive compulsive disorder and schizophrenia. However, it remains to be determined whether abnormalities in Rap1 are specifically related to affective disorders or may also be present in schizophrenia and obsessive compulsive disorder. Thus, we investigated Rap1 in platelets from 12 drug-free patients with obsessive compulsive disorder, ten drug-free patients with schizophrenia, and 20 healthy subjects. While no difference was observed in the levels of Rap1 between groups, the phosphorylation state of Rap1 was significantly lower in patients with obsessive compulsive disorder than in schizophrenic patients and controls. These data further support the idea that abnormalities of CAMP signalling pathway could be associated, albeit in a somewhat different way, with several psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 14 | Eur Neuropsychopharmacol 2001 Jun 11: 221-5 |
| PMID | 11418282 |
| Title | The cAMP-dependent protein kinase substrate Rap1 in platelets from patients with obsessive compulsive disorder or schizophrenia. |
| Abstract | Previous studies have reported that the CAMP-dependent protein kinase and one of its substrates, namely Rap1, are altered in patients with affective disorders. Abnormalities in the CAMP-dependent protein kinase have also been reported in platelets of patients with obsessive compulsive disorder and schizophrenia. However, it remains to be determined whether abnormalities in Rap1 are specifically related to affective disorders or may also be present in schizophrenia and obsessive compulsive disorder. Thus, we investigated Rap1 in platelets from 12 drug-free patients with obsessive compulsive disorder, ten drug-free patients with schizophrenia, and 20 healthy subjects. While no difference was observed in the levels of Rap1 between groups, the phosphorylation state of Rap1 was significantly lower in patients with obsessive compulsive disorder than in schizophrenic patients and controls. These data further support the idea that abnormalities of CAMP signalling pathway could be associated, albeit in a somewhat different way, with several psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 15 | Pharmacogenomics J. 2001 -1 1: 78-83 |
| PMID | 11913732 |
| Title | G649, an allelic variant of the human H2 receptor with low basal activity, is resistant to upregulation upon antagonist exposure. |
| Abstract | Orange et al reported an allelic variant of the human histamine H2 receptor, in which adenine 649 was replaced with guanine, to be more frequent in the schizophrenic population than controls in British Caucasians. The A649 to G change causes an Asn to Asp transition at amino acid position 217 in the third intracellular region, which is postulated to be important for receptor function. Herein, we analyzed the functional significance of this variant using wild-type and variant receptors expressed in Chinese hamster ovary cells. The variant receptor was associated with markedly lower basal CAMP productions than the wild-type receptor. Histamine-dependent CAMP productions via the variant receptor were lower as well. Treatment of cells expressing variant receptors with 10(-5) M ranitidine for 24 h resulted in a reduced degree of receptor upregulation as compared with the wild-type receptor. Thus, this is the first report of an allelic variant of the human H2 receptor which confers altered receptor function. To analyze gastric acid secretion in individuals with this variant, we examined 100 Japanese control subjects. However, neither heterozygotes nor homozygotes were found, suggesting that this variant, if present, is uncommon in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 16 | Psychopharmacol Bull 2002 -1 36: 92-105 |
| PMID | 12858148 |
| Title | Signal transduction abnormalities in schizophrenia: the cAMP system. |
| Abstract | Understanding the neurochemistry of schizophrenia involves the study, not only of neurotransmitters and their receptors, but also of the signal transduction systems that translate their actions into neural activity. Of particular interest is the signal transduction system involving the second messenger cyclic adenosine monophosphate (CAMP), as all dopamine receptors are either positively or negatively coupled to this system. Studies in blood platelets, cerebrospinal fluid, or postmortem brains of patients with schizophrenia demonstrate abnormalities of stimulated CAMP production. Neuroleptic administration in animal models results in altered CAMP metabolism in a pattern opposite to that seen in schizophrenic patients. These studies suggest that abnormal signal transduction may be involved in the pathogenesis of schizophrenia and that the normalization of this defect may be one mechanism of action of neuroleptic drugs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 17 | Neurochem. Res. 2002 Oct 27: 1049-63 |
| PMID | 12462404 |
| Title | Gene expression profiling with DNA microarrays: advancing our understanding of psychiatric disorders. |
| Abstract | DNA microarray transcriptome profiling of the postmortem brain opens novel horizons in understanding molecular changes associated with complex psychiatric disorders. With careful analysis and interpretation of microarray data we are uncovering previously unknown, expression patterns that maybe subject-specific and pivotal in understanding the disease process. In our recent studies, analyses of the prefrontal cortex of subjects with schizophrenia and matched controls uncovered complex changes in the expression of genes related to presynaptic secretory release, GABAergic and glutamatergic transmission, metabolic pathways, myelination, as well as CAMP and phosphoinositol second messenger systems. Our goal will be to integrate this expression data within the context of the relevant anatomical, biochemical, molecular, imaging and clinical findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 18 | Neuropsychopharmacology 2002 Apr 26: 537-45 |
| PMID | 11927178 |
| Title | Novel factor-based symptom scores in treatment resistant schizophrenia: implications for clinical trials. |
| Abstract | To study the factor structure of symptoms in patients with treatment resistant schizophrenia and whether it is altered by treatment, we analyzed ratings on the Brief Psychiatric Rating Scale (BPRS) from two independent groups of patients with treatment resistant schizophrenia. With confirmatory factor analysis of pre-clozapine BPRS scores in 1074 patients in an administrative data base, the Clozapine Authorization and Monitoring Program (CAMP), we assessed the fit of published factor models and developed a better-fitting model. Model fit was validated in an independent group of 197 research unit participants. Stability of model fit six months post-clozapine was assessed in 834 CAMP patients. A new 4-factor model (negative symptoms, reality distortion, disorganization, and anxiety/depression) had better fit in both data sets than two commonly used factor models, and also fit better post-clozapine. We recommend these four factor scores as clinical trial outcomes in patients with treatment resistant schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 19 | Psychopharmacol Bull 2002 -1 36: 92-105 |
| PMID | 12858148 |
| Title | Signal transduction abnormalities in schizophrenia: the cAMP system. |
| Abstract | Understanding the neurochemistry of schizophrenia involves the study, not only of neurotransmitters and their receptors, but also of the signal transduction systems that translate their actions into neural activity. Of particular interest is the signal transduction system involving the second messenger cyclic adenosine monophosphate (CAMP), as all dopamine receptors are either positively or negatively coupled to this system. Studies in blood platelets, cerebrospinal fluid, or postmortem brains of patients with schizophrenia demonstrate abnormalities of stimulated CAMP production. Neuroleptic administration in animal models results in altered CAMP metabolism in a pattern opposite to that seen in schizophrenic patients. These studies suggest that abnormal signal transduction may be involved in the pathogenesis of schizophrenia and that the normalization of this defect may be one mechanism of action of neuroleptic drugs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 20 | J. Pharmacol. Exp. Ther. 2002 Jul 302: 1-7 |
| PMID | 12065693 |
| Title | Molecular mechanisms for heterologous sensitization of adenylate cyclase. |
| Abstract | The nine membrane-bound isoforms of the enzyme adenylate cyclase (EC 4.6.1.1) are highly regulated by neurotransmitters and drugs acting through G protein-coupled receptors to modulate intracellular CAMP levels. In general, acute activation of Galpha(s)-coupled receptors stimulates CAMP accumulation, whereas acute activation of Galpha(i/o)-coupled receptors typically inhibits CAMP accumulation. It is also well established that persistent activation of G-protein coupled receptors will alter subsequent drug-modulated CAMP accumulation. These alterations are thought to represent cellular adaptive responses following prolonged receptor activation. One phenomenon commonly observed, heterologous sensitization of adenylate cyclase, is characterized by an enhanced responsiveness to drug-stimulated CAMP accumulation following persistent activation of Galpha(i/o)-coupled receptors. Heterologous sensitization of adenylate cyclase was originally proposed to explain tolerance and withdrawal following chronic opiate administration and may be a mechanism by which cells adapt to prolonged activation of inhibitory receptors. Such an adaptive mechanism has been suggested to play a role in the processes of addiction to and withdrawal from many drugs of abuse and in psychiatric disorders including schizophrenia and depression. Although the precise mechanisms remain unknown, research over the last decade has led to advances toward understanding the molecular events associated with heterologous sensitization of recombinant and endogenous adenylate cyclases in cellular models. These events include the pertussis toxin-sensitive events that are associated with the development of heterologous sensitization and the more recently identified Galpha(s)-dependent events that are involved in the expression of heterologous sensitization. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 21 | Science 2003 Nov 302: 1412-5 |
| PMID | 14631045 |
| Title | Diverse psychotomimetics act through a common signaling pathway. |
| Abstract | Three distinct classes of drugs: dopaminergic agonists (such as D-amphetamine), serotonergic agonists (such as LSD), and glutamatergic antagonists (such as PCP) all induce psychotomimetic states in experimental animals that closely resemble schizophrenia symptoms in humans. Here we implicate a common signaling pathway in mediating these effects. In this pathway, dopamine- and an adenosine 3',5'-monophosphate (CAMP)-regulated phospho-protein of 32 kilodaltons (DARPP-32) is phosphorylated or dephosphorylated at three sites, in a pattern predicted to cause a synergistic inhibition of protein phosphatase-1 and concomitant regulation of its downstream effector proteins glycogen synthesis kinase-3 (GSK-3), CAMP response element-binding protein (CREB), and c-Fos. In mice with a genetic deletion of DARPP-32 or with point mutations in phosphorylation sites of DARPP-32, the effects of D-amphetamine, LSD, and PCP on two behavioral parameters-sensorimotor gating and repetitive movements-were strongly attenuated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 22 | Eur. J. Pharmacol. 2003 Feb 462: 33-40 |
| PMID | 12591093 |
| Title | alpha2C-Adrenoceptor blockade by clozapine and other antipsychotic drugs. |
| Abstract | The noradrenergic system may play a role in antipsychotic modulation of schizophrenia symptoms. Therefore, the antagonistic potencies of the antipsychotics clozapine, chlorpromazine, risperidone, olanzapine, haloperidol, quetiapine, ziprasidone, iloperidone and aripiprazole were quantified using cell lines expressing the recombinant human alpha(2C)-adrenoceptor, alpha(2A)-adrenoceptor, or dopamine D(2L) receptor. The alpha(2)-adrenoceptor antagonists, yohimbine and idazoxan, were also tested. Alterations in CAMP were measured as changes in luminescence. In the alpha(2A)-adrenoceptor cell line, the agonist 5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline (UK14,304) induced a concentration-dependent increase in luminescence. In cell lines expressing alpha(2C) and D(2L) receptors, agonists induced a concentration-dependent reduction in luminescence. Yohimbine and idazoxan were the most potent alpha(2A)-adrenoceptor antagonists, yohimbine and iloperidone were the most potent alpha(2C)-adrenoceptor antagonists, and haloperidol and olanzapine were the most potent dopamine D(2) receptor antagonists. Clozapine had the highest alpha(2C)/D(2) selectivity, and iloperidone the highest alpha(2C)/alpha(2A) ratio. It is hypothesised that alpha(2C)-adrenoceptor blockade contributes to improvement of cognitive function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 23 | J. Neurosci. 2003 Apr 23: 2686-95 |
| PMID | 12684454 |
| Title | Dopamine D1-class receptors selectively modulate a slowly inactivating potassium current in rat medial prefrontal cortex pyramidal neurons. |
| Abstract | The dopamine (DA) innervation of medial prefrontal cortex (mPFC) regulates cognitive activity in a complex manner. Alterations of DA function, particularly via the DA D1 receptor class (D1R), are implicated in both schizophrenia and drug addiction, yet the precise roles of DA in modulating mPFC excitability remain unclear. We focused on DA modulation of voltage-gated K(+) current (VGKC) in acutely dissociated rat mPFC pyramidal neurons. We defined three components of the whole-cell VGKC according to biophysical and pharmacological properties. The A-type current (I(A)), with rapid activation and inactivation kinetics, was completely inactivated by prolonged holding of the membrane potential at -40 mV and was sensitive to the K(+) channel blocker 4-aminopyridine (4-AP) but not tetraethylammonium (TEA) or dendrotoxin (DTX). The slowly inactivating K(+) current (I(D)), with rapid activation but relatively slow inactivation, was the major contributor to VGKC and was completely inactivated at -40 mV and sensitive to TEA and DTX but less so to 4-AP. The very slowly inactivating K(+) current (I(K)) was elicited by command steps to more depolarized potentials from a prolonged holding potential of -40 mV and was sensitive to all three blockers. Stimulation of DA D2 receptors failed to alter any component of whole-cell VGKC. Stimulation of DA D1Rs selectively suppressed I(D), an effect mimicked by the adenylyl cyclase activator forskolin, the active CAMP analog Sp-CAMP, and the protein phosphatase inhibitor okadaic acid. Inhibition of protein kinase A (PKA) with either PKI or Rp-CAMP abolished D1R modulation. Thus, the DA D1R/CAMP/PKA signaling pathway mediates modulation of I(D) by DA in rat mPFC pyramidal neurons. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 24 | J. Pharmacol. Exp. Ther. 2003 Apr 305: 131-42 |
| PMID | 12649361 |
| Title | L-homocysteine sulfinic acid and other acidic homocysteine derivatives are potent and selective metabotropic glutamate receptor agonists. |
| Abstract | Moderate hyperhomocysteinemia is associated with several diseases, including coronary artery disease, stroke, Alzheimer's disease, schizophrenia, and spina bifida. However, the mechanisms for their pathogenesis are unknown but could involve the interaction of homocysteine or its metabolites with molecular targets such as neurotransmitter receptors, channels, or transporters. We discovered that L-homocysteine sulfinic acid (L-HCSA), L-homocysteic acid, L-cysteine sulfinic acid, and L-cysteic acid are potent and effective agonists at several rat metabotropic glutamate receptors (mGluRs). These acidic homocysteine derivatives 1) stimulated phosphoinositide hydrolysis in the cells stably expressing the mGluR1, mGluR5, or mGluR8 (plus Galpha(qi9)) and 2) inhibited the forskolin-induced CAMP accumulation in the cells stably expressing mGluR2, mGluR4, or mGluR6, with different potencies and efficacies depending on receptor subtypes. Of the four compounds, L-HCSA is the most potent agonist at mGluR1, mGluR2, mGluR4, mGluR5, mGluR6, and mGluR8. The effects of the four agonists were selective for mGluRs because activity was not discovered when L-HCSA and several other homocysteine derivatives were screened against a large panel of cloned neurotransmitter receptors, channels, and transporters. These findings imply that mGluRs are candidate G-protein-coupled receptors for mediating the intracellular signaling events induced by acidic homocysteine derivatives. The relevance of these findings for the role of mGluRs in the pathogenesis of homocysteine-mediated phenomena is discussed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 25 | Pharmacogenetics 2003 Feb 13: 119-26 |
| PMID | 12563181 |
| Title | Impairment of signal transduction in response to stimulation of the naturally occurring Pro279Leu variant of the h5-HT7(a) receptor. |
| Abstract | The aim of this study, performed in stably transfected HEK293 cells, was to investigate whether expression of the naturally occurring Pro279Leu variant of the h5-HT7(a) receptor (located in the third intracellular loop) is associated with changes in the pharmacological properties and/or second messenger formation compared to the wild-type receptor. Radioligand binding of [3H]5-carboxamidotryptamine ([3H]5-CT) to membranes and stimulation of [3H]CAMP formation in whole cells evoked by 5-HT receptor agonists were determined. Maximum binding (B(max)) to, and affinity (K(D)) of [3H]5-CT for, the variant receptor and the wild-type receptor were equal. All agonists and antagonists investigated exhibited no differences in affinity between the variant receptor and the wild-type receptor. However, the intrinsic activity of the 5-HT receptor agonists 5-HT, 5-CT, RU24969 and 8-OH-DPAT in stimulating [3H]CAMP accumulation in the cells expressing the Pro279Leu variant was almost abolished and their potency was 2.9-4.3-fold lower. Despite its affinity for both receptor isoforms, sumatriptan did not stimulate the accumulation of CAMP. In individuals expressing the Pro279Leu variant of the h5-HT7(a) receptor, a considerable attenuation of its function may be predicted. This may have relevance for the action of new classes of drugs which affect circadian rhythm or psychiatric diseases, such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 26 | Neuroscience 2004 -1 129: 101-7 |
| PMID | 15489033 |
| Title | Phosphodiesterase inhibitors: a novel mechanism for receptor-independent antipsychotic medications. |
| Abstract | All current antipsychotic medications work by binding to Gi-coupled dopamine (DA) D2 receptors. Such medications are thought to affect cellular function primarily by decreasing DA-mediated regulation of intracellular cyclic adenosine monophosphate (CAMP).However, several studies indicate that CAMP signal transduction abnormalities in schizophrenia may not be limited to D2-containing cells. The current study examines the potential of using non-receptor-based agents that modify intracellular signal transduction as potential antipsychotic medications. The indirect DA agonist amphetamine has been used to model the auditory sensory processing deficits in schizophrenia. Such pharmacologically induced abnormalities are reversed by current antipsychotic treatments. This study examines the ability of the phosphodiesterase-4 inhibitor, rolipram, to reverse amphetamine-induced abnormalities in auditory-evoked potentials that are characteristic of schizophrenia. Rolipram reverses amphetamine-induced reductions in auditory-evoked potentials. This finding could lead to novel approaches to receptor-independent treatments for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 27 | Proc. Natl. Acad. Sci. U.S.A. 2004 Apr 101: 5099-104 |
| PMID | 15044694 |
| Title | Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. |
| Abstract | Dopamine (DA) is a neurotransmitter involved in the control of locomotion, emotion, cognition, and reward. Administration of lithium salts is known to inhibit DA-associated behaviors in experimental animal models through unknown mechanisms. Here, we used a pharmacogenetic approach to show that DA can exert its behavioral effects by acting on a lithium-sensitive signaling cascade involving Akt/PKB and glycogen synthase kinase 3 (GSK-3). In the mouse striatum, increased DA neurotransmission arising either from administration of amphetamine or from the lack of the DA transporter results in inactivation of Akt and concomitant activation of GSK-3alpha and GSK-3beta. These biochemical changes are not affected by activation of the CAMP pathway but are effectively reversed either by inhibition of DA synthesis, D2 receptor blockade, or administration of lithium salts. Furthermore, pharmacological or genetic inhibition of GSK-3 significantly reduces DA-dependent locomotor behaviors. These data support the involvement of GSK-3 as an important mediator of DA and lithium action in vivo and suggest that modulation of the Akt/GSK-3 pathway might be relevant to DA-related disorders, such as attention deficit hyperactivity disorder and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 28 | Neuropsychopharmacology 2004 Oct 29: 1823-30 |
| PMID | 15138441 |
| Title | Repeated quinpirole treatment increases cAMP-dependent protein kinase activity and CREB phosphorylation in nucleus accumbens and reverses quinpirole-induced sensorimotor gating deficits in rats. |
| Abstract | Sensorimotor gating, which is severely disrupted in schizophrenic patients, can be measured by assessing prepulse inhibition of the acoustic startle response (PPI). Acute administration of D2-like receptor agonists such as quinpirole reduces PPI, but tolerance occurs upon repeated administration. In the present study, PPI in rats was reduced by acute quinpirole (0.1 mg/kg, s.c.), but not following repeated quinpirole treatment once daily for 28 days. Repeated quinpirole treatment did not alter the levels of basal-, forskolin- (5 microM), or SKF 82958- (10 microM) stimulated adenylate cyclase activity in the nucleus accumbens (NAc), but significantly increased CAMP-dependent protein kinase (PKA) activity. Phosphorylation of CAMP response element-binding protein (CREB) was significantly greater in the NAc after repeated quinpirole treatment than after repeated saline treatment with or without acute quinpirole challenge. Activation of PKA by intra-accumbens infusion of the CAMP analog, Sp-CAMPS, prevented acute quinpirole-induced PPI disruption, similar to the behavioral effect observed following repeated quinpirole treatment. Thus, repeated quinpirole treatment increases NAc PKA activity and CREB phosphorylation, and this neuroadaptive response might facilitate the recovery of sensorimotor gating in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 29 | Biol. Psychiatry 2004 Mar 55: 570-7 |
| PMID | 15013825 |
| Title | Amygdala cyclic adenosine monophosphate response element binding protein phosphorylation in patients with mood disorders: effects of diagnosis, suicide, and drug treatment. |
| Abstract | Signal transduction abnormalities have been identified in patients with bipolar (BD) and major depressive (MDD) disorders and are targets for lithium and antidepressant drugs. A key downstream target for signal transduction pathways is the transcription factor cyclic adenosine monophosphate (CAMP) response element binding protein (CREB). Therefore, we measured the levels of phosphorylated CREB (pCREB) in the amygdala, a region critical to emotional processing and important in the pathophysiology of both BD and MDD. Human postmortem amygdala sections were generously provided by the Stanley Foundation Neuropathology Consortium. Samples consisted of subjects with MDD, BD, schizophrenia (SCZ), and nonpsychiatric-nonneurologic comparison subjects (n = 15 per group). Levels of pCREB were measured by immunohistochemistry, relative to total cell number. There were no differences between diagnostic groups--control subjects and subjects with BD, MDD, or SCZ--but increased numbers of pCREB stained cells were found in several amygdalar nuclei in subjects who had died by suicide. In contrast, patients treated with lithium at the time of death had significantly lower pCREB levels in the same region. These results suggest that CREB activity may be an important factor in the neurobiology of suicide and the well-documented antisuicidal effect of lithium. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 30 | Proc. Natl. Acad. Sci. U.S.A. 2004 Feb 101: 2191-6 |
| PMID | 14769920 |
| Title | Cyclin-dependent kinase 5 regulates dopaminergic and glutamatergic transmission in the striatum. |
| Abstract | Dopaminergic and glutamatergic neurotransmissions in the striatum play an essential role in motor- and reward-related behaviors. Dysfunction of these neurotransmitter systems has been found in Parkinson's disease, schizophrenia, and drug addiction. Cyclin-dependent kinase 5 (CDK5) negatively regulates postsynaptic signaling of dopamine in the striatum. This kinase also reduces the behavioral effects of cocaine. Here we demonstrate that, in addition to a postsynaptic role, CDK5 negatively regulates dopamine release in the striatum. Inhibitors of CDK5 increase evoked dopamine release in a way that is additive to that of cocaine. This presynaptic action of CDK5 also regulates glutamatergic transmission. Indeed, inhibition of CDK5 increases the activity and phosphorylation of N-methyl-d-aspartate receptors, and these effects are reduced by a dopamine D1 receptor antagonist. Using mice with a point mutation of the CDK5 site of the postsynaptic protein DARPP-32 (dopamine- and CAMP-regulated phosphoprotein, molecular mass of 32 kDa), in the absence or in the presence of a dopamine D1 receptor antagonist, we provide evidence that CDK5 inhibitors potentiate dopaminergic transmission at both presynaptic and postsynaptic locations. These findings, together with the known ability of CDK5 inhibitors to prevent degeneration of dopaminergic neurons, suggest that this class of compounds could potentially be used as a novel treatment for disorders associated with dopamine deficiency, such as Parkinson's disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 31 | J. Neurosci. 2004 Feb 24: 1149-58 |
| PMID | 14762133 |
| Title | Regulation of dopamine D1 receptor function by physical interaction with the NMDA receptors. |
| Abstract | Functional interactions between dopamine D1-like receptors and NMDA subtype glutamate receptors have been implicated in the maintenance of normal brain activity and neurological dysfunction. Although modulation of NMDA receptor functions by D1 receptor activation has been the subject of extensive investigation, little is known as to how the activation of NMDA receptors alters D1 function. Here we report that NMDA receptors regulate D1 receptor function via a direct protein-protein interaction mediated by the carboxyl tail regions of both receptors. In both cotransfected cells and cultured hippoCAMPal neurons the activation of NMDA receptors increases the number of D1 receptors on the plasma membrane surface and enhances D1 receptor-mediated CAMP accumulation via a SNARE-dependent mechanism. Furthermore, overexpression of mini-genes encoding either NR1 or D1 carboxyl tail fragments disrupts the D1-NR1 direct protein-protein interaction and abolishes NMDA-induced changes in both D1 cell surface expression and D1-mediated CAMP accumulation. Our results demonstrate that the D1-NR1 physical interaction enables NMDA receptors to increase plasma membrane insertion of D1 receptors and provides a novel mechanism by which the activation of NMDA receptors upregulates D1 receptor function. Understanding the molecular mechanisms by which D1 and NMDA receptors functionally interact may provide insight toward elucidating the molecular neurobiological mechanisms involved in many neuropsychiatric illnesses, such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 32 | Neuropsychopharmacology 2004 Mar 29: 494-501 |
| PMID | 14694347 |
| Title | Sensorimotor gating deficits in transgenic mice expressing a constitutively active form of Gs alpha. |
| Abstract | schizophrenia is a complex disorder characterized by wide-ranging cognitive impairments, including deficits in learning as well as sensory gating. The causes of schizophrenia are unknown, but alterations in intracellular G-protein signaling pathways are among the molecular changes documented in patients with schizophrenia. Using the CaMKIIalpha promoter to drive expression in neurons within the forebrain, we have developed transgenic mice that express a constitutively active form of G(s)alpha (G(s)alpha(*)), the G protein that couples receptors such as the D(1) and D(5) dopamine receptors to adenylyl cyclase. We have also generated mice in which the CaMKIIalpha promoter drives expression of a dominant-negative form of protein kinase A, R(AB). Here, we examine startle responses and prepulse inhibition of the startle reflex (PPI) in these G(s)alpha(*) and R(AB) transgenic mice. G(s)alpha(*) transgenic mice exhibited selective deficits in PPI, without exhibiting alterations in the startle response, whereas no deficit in startle or PPI was found in the R(AB) transgenic mice. Thus, overstimulation of the CAMP/PKA pathway disrupts PPI, but the CAMP/PKA pathway may not be essential for sensorimotor gating. G(s)alpha(*) transgenic mice may provide an animal model of certain endophenotypes of schizophrenia, because of the similarities between them and patients with schizophrenia in G-protein function, hippoCAMPus-dependent learning, and sensorimotor gating. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 33 | Neuropsychopharmacology 2004 Oct 29: 1823-30 |
| PMID | 15138441 |
| Title | Repeated quinpirole treatment increases cAMP-dependent protein kinase activity and CREB phosphorylation in nucleus accumbens and reverses quinpirole-induced sensorimotor gating deficits in rats. |
| Abstract | Sensorimotor gating, which is severely disrupted in schizophrenic patients, can be measured by assessing prepulse inhibition of the acoustic startle response (PPI). Acute administration of D2-like receptor agonists such as quinpirole reduces PPI, but tolerance occurs upon repeated administration. In the present study, PPI in rats was reduced by acute quinpirole (0.1 mg/kg, s.c.), but not following repeated quinpirole treatment once daily for 28 days. Repeated quinpirole treatment did not alter the levels of basal-, forskolin- (5 microM), or SKF 82958- (10 microM) stimulated adenylate cyclase activity in the nucleus accumbens (NAc), but significantly increased CAMP-dependent protein kinase (PKA) activity. Phosphorylation of CAMP response element-binding protein (CREB) was significantly greater in the NAc after repeated quinpirole treatment than after repeated saline treatment with or without acute quinpirole challenge. Activation of PKA by intra-accumbens infusion of the CAMP analog, Sp-CAMPS, prevented acute quinpirole-induced PPI disruption, similar to the behavioral effect observed following repeated quinpirole treatment. Thus, repeated quinpirole treatment increases NAc PKA activity and CREB phosphorylation, and this neuroadaptive response might facilitate the recovery of sensorimotor gating in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 34 | Neuropsychopharmacology 2004 Mar 29: 589-97 |
| PMID | 14647483 |
| Title | ATF2, a member of the CREB/ATF family of transcription factors, in chronic stress and consequent to antidepressant treatment: animal models and human post-mortem brains. |
| Abstract | The regulation of gene expression has been implicated in the etiology and treatment of depression. Transcription factors serve as the intermediates between intracellular cascades and gene expression, and may therefore be involved in the pathophysiology and pharmacotherapy of depression. We and others have previously reported an increase in the phosphorylation of the transcription factor CAMP response element binding protein (CREB) by antidepressants, alongside brain region-specific alterations in pCREB by stress. In the present study, we examined the expression of another member of the CREB/ATF family of transcription factors, ATF2, in the brains of rats chronically treated with two different antidepressants, and in rats 4 months after their exposure to prolonged stress. ATF2 phosphorylation was decreased by antidepressants and increased at the aftermath of prolonged stress, specifically in the frontal cortex. We also examined ATF2 expression in the ventral parieto-occipital region of post-mortem human brains of normal controls, depressed, bipolar, and schizophrenic patients, obtained from the Stanley Foundation Brain Consortium. No alterations were observed in the levels of ATF2. However, in the depressed group, the pATF2 levels were higher in unmedicated compared to medicated patients, suggesting an antidepressant-induced reduction in pATF2. We discuss the possible role of ATF2 in depression, and propose that an interplay between ATF2 and CREB, and possibly other transcription factors, determines the final gene expression pattern in the etiology and treatment of depression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 35 | Brain Res. 2005 Nov 1063: 32-9 |
| PMID | 16271709 |
| Title | Quetiapine reverses the suppression of hippocampal neurogenesis caused by repeated restraint stress. |
| Abstract | Quetiapine is an atypical antipsychotic effective in treating the positive, negative, and cognitive symptoms of patients with schizophrenia. Our previous study has shown that chronic administration of quetiapine attenuates the decrease in levels of brain-derived neurotrophic factor (BDNF) in the hippoCAMPi of rats subjected to chronic-restraint stress. In the present study, we investigated the effects of quetiapine on hippoCAMPal neurogenesis that had been compromised in stressed rats. Newborn cells in the hippoCAMPus were labeled by bromodeoxyuridine (BrdU), and immature neurons were detected immunohistochemically using an antibody against phosphorylated CAMP response element-binding protein (pCREB). The restrained rats (4 h/day for 7 days) showed lower levels of hippoCAMPal neurogenesis indicated by decreased numbers of BrdU-labeled and pCREB-positive cells. Post-stress administration of quetiapine (10 mg/kg) for 7 or 21 days reversed the stress-induced suppression of hippoCAMPal neurogenesis, evidenced in the numbers of BrdU-labeled and pCREB-positive cells that are comparable to those in non-stressed rats but higher than those in the vehicle-treated rats. The results may help us understand the therapeutic effects of quetiapine on cognitive deficits in patients with schizophrenia and depression, in which the structure and functions of the hippoCAMPus are implicated. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 36 | Science 2005 Nov 310: 1187-91 |
| PMID | 16293762 |
| Title | DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. |
| Abstract | The disrupted in schizophrenia 1 (DISC1) gene is a candidate susceptibility factor for schizophrenia, but its mechanistic role in the disorder is unknown. Here we report that the gene encoding phosphodiesterase 4B (PDE4B) is disrupted by a balanced translocation in a subject diagnosed with schizophrenia and a relative with chronic psychiatric illness. The PDEs inactivate adenosine 3',5'-monophosphate (CAMP), a second messenger implicated in learning, memory, and mood. We show that DISC1 interacts with the UCR2 domain of PDE4B and that elevation of cellular CAMP leads to dissociation of PDE4B from DISC1 and an increase in PDE4B activity. We propose a mechanistic model whereby DISC1 sequesters PDE4B in resting cells and releases it in an activated state in response to elevated CAMP. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 37 | Cell 2005 Jul 122: 261-73 |
| PMID | 16051150 |
| Title | An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. |
| Abstract | Dopamine plays an important role in the etiology of schizophrenia, and D2 class dopamine receptors are the best-established target of antipsychotic drugs. Here we show that D2 class-receptor-mediated Akt regulation involves the formation of signaling complexes containing beta-arrestin 2, PP2A, and Akt. beta-arrestin 2 deficiency in mice results in reduction of dopamine-dependent behaviors, loss of Akt regulation by dopamine in the striatum, and disruption of the dopamine-dependent interaction of Akt with its negative regulator, protein phosphatase 2A. Importantly, canonical CAMP-mediated dopamine-receptor signaling is not inhibited in the absence of beta-arrestin 2. These results demonstrate that, apart from its classical function in receptor desensitization, beta-arrestin 2 also acts as a signaling intermediate through a kinase/phosphatase scaffold. Furthermore, this function of beta-arrestin 2 is important for the expression of dopamine-associated behaviors, thus implicating beta-arrestin 2 as a positive mediator of dopaminergic synaptic transmission and a potential pharmacological target for dopamine-related psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 38 | Eur. J. Pharmacol. 2005 May 515: 10-9 |
| PMID | 15894311 |
| Title | Aripiprazole's low intrinsic activities at human dopamine D2L and D2S receptors render it a unique antipsychotic. |
| Abstract | Aripiprazole is the first clinically approved atypical antipsychotic agent having dopamine D2 receptor partial agonist activities. To evaluate aripiprazole's agonist and antagonist properties, we established a Chinese hamster ovary cell line expressing high and low densities of the long and short isoforms of human dopamine D2 receptors, then compared its properties with 7-{3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy}-2(1H)-quinolinone (OPC-4392), S(-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine ((-)-3-PPP), and terguride (other partial agonists) using forskolin-stimulated CAMP accumulation as an index. In cells expressing high receptor densities, all partial agonists predominantly behaved as agonists. However, in cells expressing low receptor densities, the partial agonists showed significantly lower maximal effects than dopamine. Aripiprazole showed the lowest intrinsic activities. In addition, all compounds blocked the action of dopamine with a maximum effect equal to that of each compound alone. Aripiprazole's low intrinsic activities may account for the clinical finding that, unlike the other partial agonists, it is substantially active against both positive and negative symptoms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 39 | Behav. Neurosci. 2005 Apr 119: 595-602 |
| PMID | 15839805 |
| Title | Rolipram attenuates MK-801-induced deficits in latent inhibition. |
| Abstract | Latent inhibition is used to examine attention and study cognitive deficits associated with schizophrenia. Research using MK-801, an N-methyl-D-aspartate (NMDA) open channel blocker, implicates glutamate receptors in acquisition of latent inhibition of cued fear conditioning. Evidence suggests an important relationship between NMDA-induced increases in cyclic adenosine monophosphate (CAMP) and learning and memory. The authors examine whether amplification of the CAMP signaling pathway by rolipram, a selective Type 4 CAMP phosphodiesterase inhibitor, reverses MK-801-induced impairments in latent inhibition. One day before training, mice were injected with MK-801, rolipram, MK-801 and rolipram, or vehicle and received 20 preexposures or no preexposures to an auditory conditioned stimulus (CS). Training consisted of 2 CS-footshock unconditioned stimulus pairings. Rolipram attenuated the disruptive effect of MK-801 on latent inhibition, which suggests a role for the CAMP signaling pathway in the task and implicates phosphodiesterase inhibition as a target for treating cognitive impairments associated with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 40 | Mol. Pharmacol. 2005 Feb 67: 400-7 |
| PMID | 15539641 |
| Title | Adenosine A2A receptor and dopamine D3 receptor interactions: evidence of functional A2A/D3 heteromeric complexes. |
| Abstract | Adenosine A(2A) and dopamine D(2) receptors have been shown previously to form heteromeric complexes and interact at the level of agonist binding, G protein coupling, and trafficking. Because dopamine D(2) and D(3) receptors show a high degree of sequence homology, A(2A) and D(3) receptors may also interact in a similar manner. The present studies with confocal microscopy showed that A(2A)-yellow fluorescent protein (YFP) and D(3)-green fluorescent protein 2 (GFP2) receptors colocalize in the plasma membrane. Furthermore, fluorescence resonance energy transfer (FRET) analysis demonstrated that A(2A)-YFP and D(3)-GFP2 receptors give a positive FRET efficiency and are thereby likely to exist as heteromeric A(2A)/D(3) receptor complexes. Saturation experiments with [(3)H]dopamine demonstrated that the A(2A) receptor agonist 4-[2-[[6-amino-9(N-ethyl-beta-d-ribofuranuronaminoamidosyl)-9H-purin-2-yl]amino]ethyl]benzenepropanoic acid (CGS-21680) reduced the affinity of the high-affinity agonist binding state of the D(3) receptor for [(3)H]dopamine. The A(2A) and D(2A) receptors seem to interact also at the level of G protein coupling, because the adenosine A(2A) receptor agonist CGS-21680 fully counteracted the D(3) receptor-mediated inhibition of a forskolin-mediated increase in CAMP levels. Taken together, when coexpressed in the same neuron, A(2A) and D(3) receptors seem to form A(2A)/D(3) heteromeric receptor complexes in which A(2A) receptors antagonistically modulate both the affinity and the signaling of the D(3) receptors. D(3) receptor is one of the therapeutic targets for treatment of schizophrenia, and therefore, the A(2A)/D(3) receptor interactions could provide an alternative antischizophrenic treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 41 | Biol. Psychiatry 2005 Apr 57: 716-25 |
| PMID | 15820228 |
| Title | Alterations in cell adhesion molecule L1 and functionally related genes in major depression: a postmortem study. |
| Abstract | Current research in depression aims to delineate genes involved in neuronal plasticity that are altered in the disease or its treatment. We have shown antidepressant induced increases in three interrelated genes, cell adhesion molecule L1 (CAM-L1), laminin, and CAMP response element binding protein (CREB), and a reciprocal decrease in these genes consequent to stress. Presently we hypothesized that CAM-L1, CREB, and laminin may be altered in post mortem brains of depressed subjects. Studies were performed in the prefrontal and in the ventral parieto-occipital cortices, of 59 brains from depressed, bipolar, and schizophrenic subjects, and normal controls, obtained from the Stanley Foundation Brain Collection. mRNA and protein levels were determined by RT-PCR and Western blot analysis, respectively. Levels of CAM-L1 and of phosphorylated CREB (pCREB) were increased in the prefrontal cortex of the depressed group, while CAM-L1, laminin and pCREB were decreased in the parieto-occipital cortex. Depressed subjects receiving antidepressants differed from subjects not receiving antidepressants in the expression of CAM-L1 and laminin in the parieto-occipital cortex, and in the expression of pCREB in the prefrontal cortex. The present findings of specific alterations in depression and antidepressant treatment particularly in CAM-L1 suggest that this gene may play an important role in the pathophysiology and treatment of depression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 42 | Psychopharmacology (Berl.) 2005 May 179: 479-88 |
| PMID | 15619121 |
| Title | Activation of a nitric-oxide-sensitive cAMP pathway with phencyclidine: elevated hippocampal cAMP levels are temporally associated with deficits in prepulse inhibition. |
| Abstract | schizophrenic patients show deficits in pre-attentive information processing as evidenced, for example, by disrupted prepulse inhibition, a measure of sensorimotor gating. A similar disruption can be observed in animals treated with the psychotomimetic agent, phencyclidine (PCP). However, the mechanism by which PCP alters brain function has not been fully elucidated. Recent studies have demonstrated that certain behavioural and neurochemical effects of PCP in rats and mice are blocked by nitric oxide (NO) synthase inhibition, suggesting an important role for NO in the effects of PCP. The aim of the present study was to investigate the effects of PCP on CAMP production in the ventral hippoCAMPus and the role of NO in these effects using in vivo microdialysis in rats. Furthermore, the effects of PCP on acoustic startle reactivity and prepulse inhibition of acoustic startle were compared with changes in CAMP levels in the ventral hippoCAMPus. Significant increases in CAMP levels were observed in the ventral hippoCAMPus following both local infusion (10(-4) mol/l and 10(-3) mol/l) and systemic administration (2 mg/kg) of PCP. The PCP-induced changes in prepulse inhibition and startle reactivity were associated in magnitude and duration with the increase in CAMP levels in the hippoCAMPus. Furthermore, systemic administration of the NO synthase inhibitor, L: -NAME (10 mg/kg), blocked both the changes in CAMP levels and the behavioural responses induced by PCP. These findings indicate that the effects of PCP on prepulse inhibition and startle reactivity are associated with an increase in CAMP levels in the ventral hippoCAMPus, and that this change in CAMP response may be linked to the production of NO. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 43 | Ann. N. Y. Acad. Sci. 2006 Nov 1086: 126-33 |
| PMID | 17185511 |
| Title | Disrupted-in-schizophrenia-1 (DISC1): a key susceptibility factor for major mental illnesses. |
| Abstract | Here we overview Disrupted-in-schizophrenia-1 (DISC1), a promising lead in studying the pathophysiology of major mental conditions. Genetic association studies reproducibly suggest involvement of DISC1 in both schizophrenia and bipolar disorder in several ethnic groups. Different from several other susceptibility genes for schizophrenia, such as neuregulin-1 and dysbindin, there are two independent pedigrees in which genetic variations of DISC1 directly segregate with major mental conditions. This uniqueness has facilitated neurobiology of DISC1, which may hopefully lead to an important breakthrough in understanding of pathophysiology of major mental conditions. DISC1 is a multifunctional protein that plays a role in neurodevelopment and cell signaling. In autopsied brains from patients with psychosis and substance abuse, change in subcellular distribution of DISC1 is observed. DISC1 interacts with phosphodiesterase (PDE) 4B that degrades cyclic AMP (CAMP), which may be a regulatory molecule for working memory in the prefrontal cortex. Knockdown expression of DISC1 in developing cerebral cortex in mouse brains leads to changes that resemble, at least in part, the pathology found in patients with schizophrenia. These results support involvement of DISC1 in the pathophysiology of major mental conditions, including schizophrenia, in several mechanisms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 44 | Biol. Psychiatry 2006 Jun 59: 1189-97 |
| PMID | 16797264 |
| Title | A review of Disrupted-In-Schizophrenia-1 (DISC1): neurodevelopment, cognition, and mental conditions. |
| Abstract | Disrupted-In-schizophrenia-1 (DISC1) is a promising candidate gene for schizophrenia (SZ) and bipolar disorder (BP), but its basic biology remains to be elucidated. Accumulating genetic evidence supports that DISC1 is associated with some aspects of cognitive functions relevant to SZ and BP. Here, we provide a summary of the current updates in biological studies of DISC1. Disrupted-In-schizophrenia-1, preferentially expressed in the forebrain, has multiple isoforms with potential posttranslational modifications. Disrupted-In-schizophrenia-1 protein occurs in multiple subcellular compartments, which include the centrosome, microtubule fractions, postsynaptic densities, actin cytoskeletal fractions, the mitochondria, and the nucleus. Recent studies have clarified that DISC1 mediates at least centrosome-dynein cascade and cyclic adenosine monophosphate (CAMP) signaling. Furthermore, both cytogenetic and cell biological studies consistently suggest that an overall loss of DISC1 function (either haploinsufficiency or dominant-negative, or both) may be associated with SZ and BP. On the basis of these findings, production of DISC1 genetically engineered mice is proposed as a promising animal model for SZ and BP. Several groups are currently generating DISC1 mice and starting to characterize them. In this review, the advantages and disadvantages of each animal model are discussed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 45 | Schizophr. Res. 2006 Oct 87: 1-5 |
| PMID | 16750903 |
| Title | Mutation analysis of DARPP-32 as a candidate gene for schizophrenia. |
| Abstract | Dopamine- and CAMP-regulated phosphoprotein of relative molecular mass 32kDa (DARPP-32) plays a pivotal role in the signal transduction of several neurotransmitters and neuromodulators that are implicated in the pathophysiology of a variety of neuropsychiatric disorders. A postmortem study reported a significantly reduced DARPP-32 expression in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia, suggesting possible involvement of DARPP-32 in the pathophysiology of schizophrenia. Hence, DARPP-32 was considered as a candidate gene for schizophrenia in this study. We first systemically searched for mutations in the DARPP-32 gene in 50 Han Chinese patients with schizophrenia from Taiwan. Five molecular variants were identified, including a C-to-G substitution (g.-2036C>G) in the putative core promoter that obliterated a predictive AP-2 transcription factor binding site, a G deletion in the untranslated exon 2 (g.1238delG), a G-to-A and an A-to-G substitutions in intron 2 (IVS2+31G>A) and intron 6 (IVS6+32A>G), respectively, and a three-base pair deletion of AGA in exon 6 that resulted in deletion of a glutamate at codon 135 (E135del). Further SNP- and haplotype-based association study in 249 patients and 273 control subjects, however, did not detect association of these markers with schizophrenia. Hence, our results suggest that the reduced DARPP-32 protein in patients with schizophrenia is unlikely caused by mutations in the DARPP-32 gene itself and the DARPP-32 gene is also unlikely a major susceptibility gene for schizophrenia. Nevertheless, the identification of these molecular variants should help the study of gene regulation and structure-function relationship of DARPP-32, and the association study of DARPP-32 gene with other neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 46 | Synapse 2006 Sep 60: 319-46 |
| PMID | 16786561 |
| Title | Psychosis pathways converge via D2high dopamine receptors. |
| Abstract | The objective of this review is to identify a target or biomarker of altered neurochemical sensitivity that is common to the many animal models of human psychoses associated with street drugs, brain injury, steroid use, birth injury, and gene alterations. Psychosis in humans can be caused by amphetamine, phencyclidine, steroids, ethanol, and brain lesions such as hippoCAMPal, cortical, and entorhinal lesions. Strikingly, all of these drugs and lesions in rats lead to dopamine supersensitivity and increase the high-affinity states of dopamine D2 receptors, or D2High, by 200-400% in striata. Similar supersensitivity and D2High elevations occur in rats born by Caesarian section and in rats treated with corticosterone or antipsychotics such as reserpine, risperidone, haloperidol, olanzapine, quetiapine, and clozapine, with the latter two inducing elevated D2High states less than that caused by haloperidol or olanzapine. Mice born with gene knockouts of some possible schizophrenia susceptibility genes are dopamine supersensitive, and their striata reveal markedly elevated D2High states; suchgenes include dopamine-beta-hydroxylase, dopamine D4 receptors, G protein receptor kinase 6, tyrosine hydroxylase, catechol-O-methyltransferase, the trace amine-1 receptor, regulator of G protein signaling RGS9, and the RIIbeta form of CAMP-dependent protein kinase (PKA). Striata from mice that are not dopamine supersensitive did not reveal elevated D2High states; these include mice with knockouts of adenosine A2A receptors, glycogen synthase kinase GSK3beta, metabotropic glutamate receptor 5, dopamine D1 or D3 receptors, histamine H1, H2, or H3 receptors, and rats treated with ketanserin or aD1 antagonist. The evidence suggests that there are multiple pathways that convergetoelevate the D2High state in brain regions and that this elevation may elicit psychosis. This proposition is supported by the dopamine supersensitivity that is a common feature of schizophrenia and that also occurs in many types of genetically altered, drug-altered, and lesion-altered animals. Dopamine supersensitivity, in turn, correlates with D2High states. The finding that all antipsychotics, traditional and recent ones, act on D2High dopamine receptors further supports the proposition. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 47 | Psychopharmacology (Berl.) 2006 Jul 187: 47-55 |
| PMID | 16767415 |
| Title | Alpha4beta2 nicotinic receptor stimulation contributes to the effects of nicotine in the DBA/2 mouse model of sensory gating. |
| Abstract | Nicotine improves the deficiencies of sensory gating function in schizophrenic patients and in dilute brown non-Agouti (DBA/2) mice. This effect of nicotine has been attributed to activation of the alpha7 nicotinic acetylcholine receptor (nAChR) subtype. The aim of this study was to determine whether the activation of another nAChR subtype, the central nervous system (CNS) prominent alpha4beta2 receptor, also contributes to the effects of nicotine on sensory gating in DBA/2 mice. Unanesthetized DBA/2 mice were treated either with nicotine, the alpha4beta2 antagonist dihydro-beta-erythroidine, the noncompetitive nAChR antagonist mecamylamine, or a combination of an antagonist and nicotine. Thereafter, gating was assessed by recording hippoCAMPal evoked potentials (EP), which were elicited by pairs of auditory clicks. The EP response to the second click, or test amplitude (TAMP), was divided by the EP response to the first click, or condition amplitude (CAMP), to derive gating T:C ratios. Nicotine significantly (p<0.05) lowered T:C ratios by 42%, while significantly increasing CAMP by 55%. After a pretreatment with dihydro-beta-erythroidine, nicotine still significantly lowered T:C ratios by 28%; however, the nicotine-induced increase of CAMP was blocked. Mecamylamine blocked the effect of nicotine on both T:C ratios and CAMP. Activation of alpha4beta2 receptors by nicotine increases CAMP. However, under conditions where alpha4beta2 receptors are blocked, nicotine still lowers T:C ratios and may improve sensory gating, possibly through the activation of other nAChR subtypes such as alpha7. These effects of nicotine on auditory EPs may be indicative of a profile that would improve information processing in schizophrenia and other CNS diseases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 48 | Psychopharmacology (Berl.) 2006 Jul 187: 47-55 |
| PMID | 16767415 |
| Title | Alpha4beta2 nicotinic receptor stimulation contributes to the effects of nicotine in the DBA/2 mouse model of sensory gating. |
| Abstract | Nicotine improves the deficiencies of sensory gating function in schizophrenic patients and in dilute brown non-Agouti (DBA/2) mice. This effect of nicotine has been attributed to activation of the alpha7 nicotinic acetylcholine receptor (nAChR) subtype. The aim of this study was to determine whether the activation of another nAChR subtype, the central nervous system (CNS) prominent alpha4beta2 receptor, also contributes to the effects of nicotine on sensory gating in DBA/2 mice. Unanesthetized DBA/2 mice were treated either with nicotine, the alpha4beta2 antagonist dihydro-beta-erythroidine, the noncompetitive nAChR antagonist mecamylamine, or a combination of an antagonist and nicotine. Thereafter, gating was assessed by recording hippoCAMPal evoked potentials (EP), which were elicited by pairs of auditory clicks. The EP response to the second click, or test amplitude (TAMP), was divided by the EP response to the first click, or condition amplitude (CAMP), to derive gating T:C ratios. Nicotine significantly (p<0.05) lowered T:C ratios by 42%, while significantly increasing CAMP by 55%. After a pretreatment with dihydro-beta-erythroidine, nicotine still significantly lowered T:C ratios by 28%; however, the nicotine-induced increase of CAMP was blocked. Mecamylamine blocked the effect of nicotine on both T:C ratios and CAMP. Activation of alpha4beta2 receptors by nicotine increases CAMP. However, under conditions where alpha4beta2 receptors are blocked, nicotine still lowers T:C ratios and may improve sensory gating, possibly through the activation of other nAChR subtypes such as alpha7. These effects of nicotine on auditory EPs may be indicative of a profile that would improve information processing in schizophrenia and other CNS diseases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 49 | J. Neurosci. 2006 Feb 26: 1604-15 |
| PMID | 16452684 |
| Title | A specific role for NR2A-containing NMDA receptors in the maintenance of parvalbumin and GAD67 immunoreactivity in cultured interneurons. |
| Abstract | Several lines of evidence suggest that a hypoglutamatergic condition may induce a phenotypic loss of cortical parvalbumin (PV)-positive GABAergic interneurons, such as that observed in brain tissue of schizophrenic subjects. However, it is not known whether the loss of PV interneurons is a consequence of the hypoglutamatergic condition or a secondary aspect of the disease. We characterized the signaling and subunit expression of NMDA receptors in cultured cortical PV interneurons and determined whether a hypoglutamatergic condition, created by direct application of sublethal concentrations of ketamine or subunit-selective NMDA receptor antagonists, can affect the expression of the GABAergic markers as observed in vivo. Real-time PCR performed on mRNA isolated from single neurons showed that PV interneurons present a fivefold higher NR2A/NR2B ratio than pyramidal neurons. Brief, nontoxic, exposure to NMDA led to an increase in ERK1/2 (extracellular signal-regulated kinase 1/2) and CAMP response element-binding protein phosphorylation in PV interneurons, and this increase was blocked by the NR2A-selective antagonist NVP-AAM077. Application of the nonselective NMDA receptor antagonist ketamine, at sublethal concentrations, induced a time and dose-dependent decrease in parvalbumin and GAD67 immunoreactivity specifically in PV interneurons. These effects were reversible and were also observed with the NR2A-selective antagonist, whereas the NR2B-selective antagonist Ro-25-6981 only partially reduced GAD67 immunoreactivity. Coexposure to the calcium channel opener BayK, or the group I metabotropic glutamate receptor agonist DHPG [(RS)-3,5-dihydroxyphenylglycine] attenuated the decrease in GAD67 and parvalbumin induced by the NMDA receptor antagonists. These results suggest that the activity of NR2A-containing NMDA receptors play a pivotal role in the maintenance of the GABAergic function of PV interneurons. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 50 | Neuropsychopharmacology 2006 Apr 31: 853-65 |
| PMID | 16205782 |
| Title | Antipsychotic drugs inhibit the human corticotropin-releasing-hormone gene promoter activity in neuro-2A cells-an involvement of protein kinases. |
| Abstract | Antipsychotic drugs can regulate transcription of some genes, including those involved in regulation of hypothalamic-pituitary-adrenal (HPA) axis, whose activity is frequently disturbed in schizophrenic patients. However, molecular mechanism of antipsychotic drug action on the corticotropin-releasing hormone (CRH) gene activity has not been investigated so far. This study was undertaken to examine the influence of conventional and atypical antipsychotic drugs on the CRH gene promoter activity in differentiated Neuro-2A cell cultures stably transfected with a human CRH promoter fragment linked to the chloramphenicol acetyltransferase (CAT) reporter gene. It has been found that chlorpromazine (0.1-5.0 microM), haloperidol (0.5-5.0 microM), clozapine (1.0-5.0 microM), thioridazine (1.0-5.0 microM), promazine (5.0 and 10 microM), risperidone (5.0 and 10.0 microM), and raclopride (only at the highest used concentrations, ie 30 and 100 microM) present in culture medium for 5 days inhibited the CRH-CAT activity. Sulpiride and remoxipride had no effect. Since CRH gene activity is most potently enhanced by CAMP/protein kinase A pathway, the effect of antipsychotics on the forskolin-induced CRH-CAT activity was determined. Chlorpromazine (1.0-5.0 microM), haloperidol (1.0-5.0 microM), clozapine (1.0-5.0 microM), thioridazine (3.0 and 5.0 microM), and raclopride (30 and 100 microM), but not promazine, sulpiride, risperidone, and remoxipride, inhibited the forskolin-stimulated CRH gene promoter activity. A possible involvement of protein kinases in chlorpromazine and clozapine inhibitory action on CRH activity was also investigated. It was found that wortmannin (0.01 and 0.02 microM), an inhibitor of phosphatidylinositol 3-kinase (PI3-K), significantly attenuated the inhibitory effect of chlorpromazine and clozapine on CRH gene promoter activity. In line with these results, a Western blot study showed that these drugs increased phospho-Ser-473 Akt level, had no effect on total Akt, and decreased glycogen synthase kinase-3beta level. Additionally, we found that clozapine decreased protein kinase C (PKC) level and that its action on CRH activity was attenuated by PKC activator (TPA, 0.1 microM). The obtained results indicate that inhibition of CRH gene promoter activity by some antipsychotic drugs may be a molecular mechanism responsible for their inhibitory action on HPA axis activity. Clozapine and chlorpromazine action on CRH activity operates mainly through activation of the PI3-K/Akt pathway. Moreover, PKC-mediated pathway seems to be involved in clozapine action on CRH gene activity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 51 | Biochem. Soc. Trans. 2007 Nov 35: 1283-6 |
| PMID | 17956330 |
| Title | Dissecting DISC1 function through protein-protein interactions. |
| Abstract | Disrupted in schizophrenia 1 (DISC1) is emerging in the eyes of many as the most promising candidate of all the schizophrenia risk genes. This viewpoint is derived from the combination of genetic, clinical, imaging and rapidly advancing cell biology data around this gene. All of these areas have been reviewed extensively recently and this review will point you towards some of these excellent papers. My own personal view of the potential importance of DISC1 was echoed in a recent review which suggested that DISC1 may be a 'Rosetta Stone' for schizophrenia research [Ross, Margolis, Reading, Pletnikov and Coyle (2006) Neuron 52, 139-153]. Our own efforts to try to understand the function of DISC1 were through identification of its protein-binding partners. Through an extensive Y2H (yeast two-hybrid) and bioinformatics effort we generated the 'DISC1-Interactome', a comprehensive network of protein-protein interactions around DISC1. In two excellent industry-academia collaborations we focused on two main interacting partners: Ndel1 (nudE nuclear distribution gene E homologue-like 1), an enigmatic protein which may have diverse functions as both a cysteine protease and a key centrosomal structural protein; and PDE4B, a CAMP-specific phosphodiesterase. I will review the work around these two protein complexes in detail. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 52 | J. Physiol. (Lond.) 2007 Oct 584: 401-5 |
| PMID | 17823207 |
| Title | Disrupted in schizophrenia 1 and phosphodiesterase 4B: towards an understanding of psychiatric illness. |
| Abstract | Disrupted in schizophrenia 1 (DISC1) is one of the most convincing genetic risk factors for major mental illness identified to date. DISC1 interacts directly with phosphodiesterase 4B (PDE4B), an independently identified risk factor for schizophrenia. DISC1-PDE4B complexes are therefore likely to be involved in molecular mechanisms underlying psychiatric illness. PDE4B hydrolyses CAMP and DISC1 may regulate CAMP signalling through modulating PDE4B activity. There is evidence that expression of both genes is altered in some psychiatric patients. Moreover, DISC1 missense mutations that give rise to phenotypes related to schizophrenia and depression in mice are located within binding sites for PDE4B. These mutations reduce the association between DISC1 and PDE4B, and one results in reduced brain PDE4B activity. Altered DISC1-PDE4B interaction may thus underlie the symptoms of some cases of schizophrenia and depression. Factors likely to influence this interaction include expression levels, binding site affinities and the DISC1 and PDE4 isoforms involved. DISC1 and PDE4 isoforms are targeted to specific subcellular locations which may contribute to the compartmentalization of CAMP signalling. Dysregulated CAMP signalling in specific cellular compartments may therefore be a predisposing factor for major mental illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 53 | J. Clin. Invest. 2007 Mar 117: 672-82 |
| PMID | 17290303 |
| Title | Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition. |
| Abstract | Dopamine- and CAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32), encoded by PPP1R1B, is a pivotal integrator of information in dopaminoceptive neurons, regulating the response to neuroleptics, psychotomimetics, and drugs of abuse, and affecting striatal function and plasticity. Despite extensive preclinical work, there are almost no data on DARPP-32 function in humans. Here, we identify, through resequencing in 298 chromosomes, a frequent PPP1R1B haplotype predicting mRNA expression of PPP1R1B isoforms in postmortem human brain. This haplotype was associated with enhanced performance on several cognitive tests that depend on frontostriatal function. Multimodal imaging of healthy subjects revealed an impact of the haplotype on neostriatal volume, activation, and the functional connectivity of the prefrontal cortex. The haplotype was associated with the risk for schizophrenia in 1 family-based association analysis. Our convergent results identify a prefrontal-neostriatal system affected by variation in PPP1R1B and suggest that DARPP-32 plays a pivotal role in cognitive function and possibly in the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 54 | Curr Opin Investig Drugs 2007 Jan 8: 54-9 |
| PMID | 17263185 |
| Title | Phosphodiesterase 10A inhibitors: a novel approach to the treatment of the symptoms of schizophrenia. |
| Abstract | A disruption of corticostriatal signaling is believed to underlie the psychotic symptoms of schizophrenia and also contribute to many of the cognitive deficits associated with this disorder. Phosphodiesterase (PDE)10A is a dual substrate PDE highly expressed in striatal medium spiny neurons. Biochemical and behavioral studies indicate that the inhibition of PDE10A enhances striatal output by increasing activity in the cGMP and CAMP signaling pathways. PDE10A inhibitors reduce exploratory activity and antagonize the stimulant response to both amphetamine and N-methyl-d-aspartate antagonists such as phencyclidine. Consistent with their potential as antipsychotic agents, PDE10A inhibitors are potent antagonists of conditioned avoidance responding. The presence of PDE10A in both striatal output pathways may reduce the incidence and severity of dopamine D2 receptor antagonist-like side effects, including extrapyramidal symptoms. In addition, by enhancing corticostriatal signaling, PDE10A inhibitors have the potential to improve some of the cognitive symptoms of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 55 | J. Neurosci. 2007 Nov 27: 12390-5 |
| PMID | 17989303 |
| Title | Evidence that the BLOC-1 protein dysbindin modulates dopamine D2 receptor internalization and signaling but not D1 internalization. |
| Abstract | The schizophrenia susceptibility gene dystrobrevin-binding protein 1 (DTNBP1) encodes dysbindin, which along with its binding partner Muted is an essential component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Dysbindin expression is reduced in schizophrenic brain tissue, but the molecular mechanisms by which this contributes to pathogenesis and symptomatology are unknown. We studied the effects of transfection of DTNBP1 siRNA on cell surface levels of dopamine D2 receptor (DRD2) in human SH-SY5Y neuroblastoma cells and in rat primary cortical neurons. DTNBP1 siRNA decreased dysbindin protein, increased cell surface DRD2 and blocked dopamine-induced DRD2 internalization. MUTED siRNA produced similar effects. In contrast, decreased dysbindin did not change dopamine D1 receptor (DRD1) levels, or its basal or dopamine-induced internalization. The DRD2 agonist quinpirole reduced phosphorylation of CREB (CAMP response element-binding protein) in dysbindin downregulated cells, demonstrating enhanced intracellular signaling caused by the upregulation of DRD2. This is the first demonstration of a schizophrenia susceptibility gene exerting a functional effect on DRD2 signaling, a pathway that has long been implicated in the illness. We propose a molecular mechanism for pathogenesis in which risk alleles in DTNBP1, or other factors that also downregulate dysbindin, compromise the ability of BLOC-1 to traffic DRD2 toward degradation, but has little effect on DRD1 trafficking. Impaired trafficking of DRD2 decreases dopamine-induced internalization, and with more receptors retained on the cell surface, dopamine stimulation produces excess intracellular signaling. Such an increase in DRD2 signaling relative to DRD1 would contribute to the imbalances in dopaminergic neurotransmission characteristic of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 56 | J. Neurosci. 2007 Sep 27: 10578-87 |
| PMID | 17898229 |
| Title | Broad-spectrum efficacy across cognitive domains by alpha7 nicotinic acetylcholine receptor agonism correlates with activation of ERK1/2 and CREB phosphorylation pathways. |
| Abstract | The alpha7 nicotinic acetylcholine receptor (nAChR) plays an important role in cognitive processes and may represent a drug target for treating cognitive deficits in neurodegenerative and psychiatric disorders. In the present study, we used a novel alpha7 nAChR-selective agonist, 2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole (A-582941) to interrogate cognitive efficacy, as well as examine potential cellular mechanisms of cognition. Exhibiting high affinity to native rat (Ki = 10.8 nM) and human (Ki = 16.7 nM) alpha7 nAChRs, A-582941 enhanced cognitive performance in behavioral assays including the monkey delayed matching-to-sample, rat social recognition, and mouse inhibitory avoidance models that capture domains of working memory, short-term recognition memory, and long-term memory consolidation, respectively. In addition, A-582941 normalized sensory gating deficits induced by the alpha7 nAChR antagonist methyllycaconitine in rats, and in DBA/2 mice that exhibit a natural sensory gating deficit. Examination of signaling pathways known to be involved in cognitive function revealed that alpha7 nAChR agonism increased extracellular-signal regulated kinase 1/2 (ERK1/2) phosphorylation in PC12 cells. Furthermore, increases in ERK1/2 and CAMP response element-binding protein (CREB) phosphorylation were observed in mouse cingulate cortex and/or hippoCAMPus after acute A-582941 administration producing plasma concentrations in the range of alpha7 binding affinities and behavioral efficacious doses. The MEK inhibitor SL327 completely blocked alpha7 agonist-evoked ERK1/2 phosphorylation. Our results demonstrate that alpha7 nAChR agonism can lead to broad-spectrum efficacy in animal models at doses that enhance ERK1/2 and CREB phosphorylation/activation and may represent a mechanism that offers potential to improve cognitive deficits associated with neurodegenerative and psychiatric diseases, such as Alzheimer's disease and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 57 | J. Neurosci. 2007 Aug 27: 9513-24 |
| PMID | 17728464 |
| Title | Isoform-selective susceptibility of DISC1/phosphodiesterase-4 complexes to dissociation by elevated intracellular cAMP levels. |
| Abstract | Disrupted-in-schizophrenia 1 (DISC1) is a genetic susceptibility factor for schizophrenia and related severe psychiatric conditions. DISC1 is a multifunctional scaffold protein that is able to interact with several proteins, including the independently identified schizophrenia risk factor phosphodiesterase-4B (PDE4B). Here we report that the 100 kDa full-length DISC1 isoform (fl-DISC1) can bind members of each of the four gene, CAMP-specific PDE4 family. Elevation of intracellular CAMP levels, so as to activate protein kinase A, caused the release of PDE4D3 and PDE4C2 isoforms from fl-DISC1 while not affecting binding of PDE4B1 and PDE4A5 isoforms. Using a peptide array strategy, we show that PDE4D3 binds fl-DISC1 through two regions found in common with PDE4B isoforms, the interaction of which is supplemented because of the presence of additional PDE4B-specific binding sites. We propose that the additional binding sites found in PDE4B1 underpin its resistance to release during CAMP elevation. We identify, for the first time, a functional distinction between the 100 kDa long DISC1 isoform and the short 71 kDa isoform. Thus, changes in the expression pattern of DISC1 and PDE4 isoforms offers a means to reprogram their interaction and to determine whether the PDE4 sequestered by DISC1 is released after CAMP elevation. The PDE4B-specific binding sites encompass point mutations in mouse Disc1 that confer phenotypes related to schizophrenia and depression and that affect binding to PDE4B. Thus, genetic variation in DISC1 and PDE4 that influence either isoform expression or docking site functioning may directly affect psychopathology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 58 | Eur. J. Pharmacol. 2007 Nov 574: 103-11 |
| PMID | 17692841 |
| Title | Differences in agonist/antagonist properties at human dopamine D(2) receptors between aripiprazole, bifeprunox and SDZ 208-912. |
| Abstract | Aripiprazole is the first dopamine D(2) receptor partial agonist approved for use in schizophrenia and bipolar disorder. Other partial agonists have failed in various stages of development, either for reasons of poor tolerability or lack of efficacy. We conducted an in vitro comparative analysis between aripiprazole, bifeprunox, SDZ 208-912, OPC-4392 and ACR16 in attempt to correlate specific pharmacological properties with clinical outcome. In vitro pharmacological assessment included inhibition of forskolin-stimulated CAMP accumulation and the reversal of this inhibition produced by dopamine in clonal CHO cell lines expressing high and low densities of human dopamine D(2L) and D(2S) receptors. In cells expressing high receptor densities, all drugs except ACR16 predominantly behaved as agonists. However, in cells expressing low receptor densities, all drugs showed significantly lower maximal effects than dopamine. Aripiprazole's intrinsic activity was lower than that observed with bifeprunox and OPC-4392, and higher than that of SDZ 208-912. Aripiprazole's antagonist activity was greater than that of bifeprunox and OPC-4392, and less than that of SDZ 208-912. In conclusion, our data suggests that aripiprazole's unique intrinsic activity profile may account for its demonstrated clinical efficacy in the treatment of both positive and negative symptoms of schizophrenia, as well as its demonstrated low liability for parkinsonism and hyperprolactinemia. A higher degree of intrinsic activity, and lower relative antagonist activity, such as that observed with bifeprunox and OPC-4392 may translate into a clinically suboptimal improvement of positive symptoms. SDZ 208-912's intrinsic activity may be lower than the optimal level needed to minimize extrapyramidal symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 59 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2007 Aug 31: 1303-6 |
| PMID | 17618027 |
| Title | An association study between PPP1R1B gene and schizophrenia in the Chinese population. |
| Abstract | schizophrenia has been linked with dysfunctions of glutamatergic, dopaminergic, and serotonergic neurotransmission. Dopamine- and CAMP-regulated phosphoprotein of relative molecular mass 32 kDa (DARPP-32), encoded by PPP1R1B (protein phosphatase 1, regulatory/inhibitor subunit 1B) gene, is enriched in neostriatal medium spiny neurons. It plays a key regulator role in dopaminergic and glutamatergic signaling pathways. The combined evidence from reduced DARPP-32 expression in the dorsolateral prefrontal cortex (DLPFC) in schizophrenic patients and from abnormalities in mice with a genetic deletion of DARPP-32 or with point mutations in phosphorylation sites of DARPP-32 suggested that it would be worthwhile to investigate the association between DARPP-32 and schizophrenia. In the present study, we genotyped five single nucleotide polymorphisms (SNPs) in the PPP1R1B gene and conducted a case-control study involving 520 schizophrenic patients and 386 healthy subjects drawn from the Chinese population. No allelic, genotypic or haplotypic association was found. However, our results do not preclude the possibility that the PPP1R1B is a susceptibility gene for schizophrenia in the Chinese population, since, as a central molecular switch, PPP1R1B may contribute to schizophrenia by interacting with other genes. Further functional analysis and genetic association studies are needed to determine the potential roles of PPP1R1B and other related genes in the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 60 | J. Pharmacol. Exp. Ther. 2007 Aug 322: 600-9 |
| PMID | 17519386 |
| Title | PDE4B5, a novel, super-short, brain-specific cAMP phosphodiesterase-4 variant whose isoform-specifying N-terminal region is identical to that of cAMP phosphodiesterase-4D6 (PDE4D6). |
| Abstract | The CAMP-specific phosphodiesterase-4 (PDE4) gene family is the target of several potential selective therapeutic inhibitors. The four PDE4 genes generate several distinct protein-coding isoforms through the use of alternative promoters and 5'-coding exons. Using mouse transcripts, we identified a novel, super-short isoform of human PDE4B encoding a novel 5' terminus, which we label PDE4B5. The protein-coding region of the novel 5' exon is conserved across vertebrates, chicken, zebrafish, and fugu. Reverse-transcription-polymerase chain reaction (PCR) and quantitative (PCR) measurements show that this isoform is brain-specific. The novel protein is 58 +/- 2 kDa; it has CAMP hydrolyzing enzymatic activity and is inhibited by PDE4-selective inhibitors rolipram and cilomilast (Ariflo). Confocal and subcellular fractionation analyses show that it is distributed predominantly and unevenly within the cytosol. The 16 novel N-terminal residues of PDE4B5 are identical to the 16 N-terminal residues of the super-short isoform of PDE4D (PDE4D6), which is also brain-specific. PDE4B5 is able to bind the scaffold protein DISC1, whose gene has been linked to schizophrenia. Microarray expression profiling of the PDE4 gene family shows that specific PDE4 genes are enriched in muscle and blood fractions; however, only by monitoring the individual isoforms is the brain specificity of the super-short PDE4D and PDE4B isoforms revealed. Understanding the distinct tissue specificity of PDE4 isoforms will be important for understanding phosphodiesterase biology and opportunities for therapeutic intervention. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 61 | Cereb. Cortex 2007 Sep 17 Suppl 1: i6-15 |
| PMID | 17434919 |
| Title | Catecholamine and second messenger influences on prefrontal cortical networks of "representational knowledge": a rational bridge between genetics and the symptoms of mental illness. |
| Abstract | Both dopamine (DA) and norepinephrine (NE) have powerful, inverted U influences on prefrontal cortical (PFC) cognitive function. Optimal NE levels engage alpha2A-adrenoceptors and increase "signals" via inhibition of CAMP-HCN (CAMP-hyperpolarization-activated cyclic nucleotide-gated cation channel) signaling near preferred inputs, whereas optimal levels of DA D1 receptor stimulation decrease "noise" by increasing CAMP signaling near nonpreferred inputs. Excessive levels of catecholamine release during stress impair working memory 1) by very high levels of CAMP-HCN signaling diminishing preferred as well as nonpreferred inputs and 2) by high levels of NE engaging alpha1 stimulation of phosphotidyl inositol (PI) signaling that suppresses cell firing. Common mental illnesses are associated with extracellular changes in these pathways: Attention Deficit Hyperactivity Disorder is linked to genetic changes that reduce catecholamine transmission to suboptimal levels and is treated with agents that increase catecholamine transmission, whereas Post-Traumatic Stress Disorder (PTSD) is associated with amplified noradrenergic transmission that impairs PFC but strengthens amygdala function. PTSD is now treated with agents that block alpha1 or beta adrenoceptors. In contrast, the more severe mental illnesses, schizophrenia and bipolar disorder, are associated with genetic changes in molecules regulating intracellular signaling pathways activated by stress. Specifically, DISC1 inhibits CAMP signaling whereas regulator of G-protein signaling 4 inhibits PI signaling. Loss of function in these genes may render patients vulnerable to profound stress-induced PFC dysfunction including symptoms of thought disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 62 | Br. J. Pharmacol. 2007 May 151: 237-52 |
| PMID | 17375087 |
| Title | F15063, a potential antipsychotic with D2/D3 antagonist, 5-HT 1A agonist and D4 partial agonist properties. I. In vitro receptor affinity and efficacy profile. |
| Abstract | Combining 5-HT(1A) receptor activation with dopamine D(2)/D(3) receptor blockade should improve negative symptoms and cognitive deficits in schizophrenia. We describe the in vitro profile of F15063 (N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)ethyl]-3-(cyclopent-1-enyl)-benzylamine). F15063 was characterised in tests of binding affinity and in cellular models of signal transduction at monoamine receptors. Affinities (receptor and pK(i) values) of F15063 were: rD(2) 9.38; hD(2L) 9.44; hD(2S) 9.25; hD(3) 8.95; hD(4) 8.81; h5-HT(1A) 8.37. F15063 had little affinity (40-fold lower than D(2)) at other targets. F15063 antagonised dopamine-activated G-protein activation at hD(2), rD(2) and hD(3) receptors with potency (pK (b) values 9.19, 8.29 and 8.74 in [(35)S]GTP gamma S binding experiments) similar to haloperidol. F15063 did not exhibit any hD(2) receptor agonism, even in tests of ERK1/2 phosphorylation and G-protein activation in cells with high receptor expression. In contrast, like (+/-)8-OH-DPAT, F15063 efficaciously activated h5-HT(1A) (E(max) 70%, pEC(50) 7.57) and r5-HT(1A) receptors (52%, 7.95) in tests of [(35)S]GTP gamma S binding, CAMP accumulation (90%, 7.12) and ERK1/2 phosphorylation (93%, 7.13). F15063 acted as a partial agonist for [(35)S]GTP gamma S binding at hD(4) (29%, 8.15) and h5-HT(1D) receptors (35%, 7.68). In [(35)S]GTP gamma S autoradiography, F15063 activated G-proteins in hippoCAMPus, cortex and septum (regions enriched in 5-HT(1A) receptors), but antagonised quinelorane-induced activation of D(2)/D(3) receptors in striatum. F15063 antagonised dopamine D(2)/D(3) receptors, a property underlying its antipsychotic-like activity, whereas activation of 5-HT(1A) and D(4) receptors mediated its actions in models of negative symptoms and cognitive deficits of schizophrenia (see companion papers). |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 63 | Neuroscience 2007 Mar 145: 900-10 |
| PMID | 17293055 |
| Title | Prefrontal cortical network activity: Opposite effects of psychedelic hallucinogens and D1/D5 dopamine receptor activation. |
| Abstract | The fine-tuning of network activity provides a modulating influence on how information is processed and interpreted in the brain. Here, we use brain slices of rat prefrontal cortex to study how recurrent network activity is affected by neuromodulators known to alter normal cortical function. We previously determined that glutamate spillover and stimulation of extrasynaptic N-methyl-d-aspartic acid (NMDA) receptors are required to support hallucinogen-induced cortical network activity. Since microdialysis studies suggest that psychedelic hallucinogens and dopamine D1/D5 receptor agonists have opposite effects on extracellular glutamate in prefrontal cortex, we hypothesized that these two families of psychoactive drugs would have opposite effects on cortical network activity. We found that network activity can be enhanced by 2,5-dimethoxy-4-iodoamphetamine (DOI) (a psychedelic hallucinogen that is a partial agonist of 5-HT(2A/2C) receptors) and suppressed by the selective D1/D5 agonist SKF 38393. This suppression could be mimicked by direct activation of adenylyl cyclase with forskolin or by addition of a CAMP analog. These findings are consistent with previous work showing that activation of adenylyl cyclase can upregulate neuronal glutamate transporters, thereby decreasing synaptic spillover of glutamate. Consistent with this hypothesis, a low concentration of the glutamate transporter inhibitor threo-beta-benzoylaspartic acid (TBOA) restored electrically-evoked recurrent activity in the presence of a selective D1/D5 agonist, whereas recurrent activity in the presence of a low level of the GABA(A) antagonist bicuculline was not resistant to suppression by the D1/D5 agonist. The tempering of network UP states by D1/D5 receptor activation may have implications for the proposed use of D1/D5 agonists in the treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 64 | J. Pharmacol. Exp. Ther. 2007 Apr 321: 308-17 |
| PMID | 17204749 |
| Title | Pharmacological and pharmacokinetic properties of a structurally novel, potent, and selective metabotropic glutamate 2/3 receptor agonist: in vitro characterization of agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic acid (LY404039). |
| Abstract | Group II metabotropic glutamate (mGlu) receptor agonists, including (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740) and (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), have demonstrated efficacy in animal models of anxiety and schizophrenia, and LY354740 decreased anxiety in human subjects. Herein, we report the in vitro pharmacological profile and pharmacokinetic properties of another potent, selective, and structurally novel mGlu2/3 receptor agonist, (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY404039) and provide comparisons with LY354740. Similar to LY354740, LY404039 is a nanomolar potent agonist at recombinant human mGlu2 and mGlu3 receptors (K(i) = 149 and 92, respectively) and in rat neurons expressing native mGlu2/3 receptors (Ki = 88). LY404039 is highly selective for mGlu2/3 receptors, showing more than 100-fold selectivity for these receptors, versus ionotropic glutamate receptors, glutamate transporters, and other receptors targeted by known anxiolytic and antipsychotic medications. Functionally, LY404039 potently inhibited forskolin-stimulated CAMP formation in cells expressing human mGlu2 and mGlu3 receptors. Electrophysiological studies indicated that LY404039 suppressed electrically evoked excitatory activity in the striatum, and serotonin-induced l-glutamate release in the prefrontal cortex; effects reversed by LY341495. These characteristics suggest LY404039 modulates glutamatergic activity in limbic and forebrain areas relevant to psychiatric disorders; and that, similar to LY354740, it works through a mechanism that may be devoid of negative side effects associated with current antipsychotics and anxiolytics. Interestingly, despite the slightly lower potency (approximately 2-5-fold) of LY404039 versus LY354740 in binding, functional, and electrophysiological assays, LY404039 demonstrated higher plasma exposure and better oral bioavailability in pharmacokinetic experiments. Collectively, the current data indicate that LY404039 may be valuable in the treatment of neuropsychiatric disorders, including anxiety and psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 65 | Psychopharmacology (Berl.) 2007 Apr 191: 783-92 |
| PMID | 17096084 |
| Title | Neonatal exposure to epidermal growth factor induces dopamine D2-like receptor supersensitivity in adult sensorimotor gating. |
| Abstract | Abnormality in the neurotrophic factor for dopamine neurons, epidermal growth factor (EGF), is associated with schizophrenia. Thus, rats treated with EGF as neonates are used as a putative animal model for schizophrenia showing impaired prepulse inhibition (PPI) and other cognitive deficits in the adult stage. To elucidate the abnormal behavioral traits of this animal model, the EGF effects on the dopaminergic system were analyzed pharmacologically and biochemically at the adult stage. We examined the effects of subthreshold doses of dopamine agonists on PPI in this model. A non-selective dopamine agonist, apomorphine (0.1 mg/kg), decreased PPI in EGF-treated rats, but not in controls. Further, a D(2)-like receptor agonist, quinpirole (0.01 and 0.03 mg/kg), similarly decreased PPI in EGF-treated rats but had no effect in the control animals. In contrast, a D(1)-like receptor agonist, SKF38393 (3 and 10 mg/kg), had no effect on PPI in both groups. To explore the molecular mechanism underlying the change in sensorimotor gating, we assessed D(1) and D(2) receptors expression in the prefrontal cortex, striatum and hippoCAMPus and their downstream signaling. Although there were no significant differences in basal receptor levels, quinpirole administration significantly enhanced phosphorylation of extracellular signal-regulated kinase (ERK) and CAMP response element binding protein (CREB) in the striatum of EGF-treated rats. These results suggest that circulating EGF in the early development substantially influences D(2) receptor-dependent regulation of sensorimotor gating. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 66 | Neuroscience 2007 Jan 144: 239-46 |
| PMID | 17081698 |
| Title | Rolipram: a specific phosphodiesterase 4 inhibitor with potential antipsychotic activity. |
| Abstract | Currently available antipsychotic medications work primarily by antagonizing D2 dopamine receptors, thus raising intracellular CAMP levels. We hypothesized that intracellular stimulation of CAMP levels in the CNS would have similar effects to treatment with antipsychotic medication. To test this hypothesis, we studied the effect of an acute treatment of rolipram, an inhibitor of type 4 phosphodiesterases that degrade CAMP, on acoustic startle and prepulse inhibition (PPI) of the acoustic startle response in C57BL/6J mice known to exhibit poor PPI. PPI is disrupted in schizophrenia patients, and the ability of a drug to increase PPI in mice is predictive of antipsychotic efficacy. We show here that acute treatment with rolipram significantly increases PPI at doses that do not alter the acoustic startle response (lowest effective dose 0.66 mg/kg). In addition, rolipram (0.66 mg/kg) blocks the disruptive effects of amphetamine (10 mg/kg) on PPI. At a slightly higher dose (1.0 mg/kg), rolipram also induces catalepsy. Thus, phosphodiesterase-4 (PDE4) inhibition has many of the same behavioral effects as traditional antipsychotic medications. In contrast to traditional antipsychotics, these effects are achieved through alteration of an intracellular second messenger system rather than antagonism of neurotransmitter receptors. Given previous reports showing rolipram improves cognition, we conclude that PDE4 represents an important novel target for further antipsychotic drug development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 67 | J. Neurosci. 2007 Nov 27: 12390-5 |
| PMID | 17989303 |
| Title | Evidence that the BLOC-1 protein dysbindin modulates dopamine D2 receptor internalization and signaling but not D1 internalization. |
| Abstract | The schizophrenia susceptibility gene dystrobrevin-binding protein 1 (DTNBP1) encodes dysbindin, which along with its binding partner Muted is an essential component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Dysbindin expression is reduced in schizophrenic brain tissue, but the molecular mechanisms by which this contributes to pathogenesis and symptomatology are unknown. We studied the effects of transfection of DTNBP1 siRNA on cell surface levels of dopamine D2 receptor (DRD2) in human SH-SY5Y neuroblastoma cells and in rat primary cortical neurons. DTNBP1 siRNA decreased dysbindin protein, increased cell surface DRD2 and blocked dopamine-induced DRD2 internalization. MUTED siRNA produced similar effects. In contrast, decreased dysbindin did not change dopamine D1 receptor (DRD1) levels, or its basal or dopamine-induced internalization. The DRD2 agonist quinpirole reduced phosphorylation of CREB (CAMP response element-binding protein) in dysbindin downregulated cells, demonstrating enhanced intracellular signaling caused by the upregulation of DRD2. This is the first demonstration of a schizophrenia susceptibility gene exerting a functional effect on DRD2 signaling, a pathway that has long been implicated in the illness. We propose a molecular mechanism for pathogenesis in which risk alleles in DTNBP1, or other factors that also downregulate dysbindin, compromise the ability of BLOC-1 to traffic DRD2 toward degradation, but has little effect on DRD1 trafficking. Impaired trafficking of DRD2 decreases dopamine-induced internalization, and with more receptors retained on the cell surface, dopamine stimulation produces excess intracellular signaling. Such an increase in DRD2 signaling relative to DRD1 would contribute to the imbalances in dopaminergic neurotransmission characteristic of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 68 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2007 Aug 31: 1303-6 |
| PMID | 17618027 |
| Title | An association study between PPP1R1B gene and schizophrenia in the Chinese population. |
| Abstract | schizophrenia has been linked with dysfunctions of glutamatergic, dopaminergic, and serotonergic neurotransmission. Dopamine- and CAMP-regulated phosphoprotein of relative molecular mass 32 kDa (DARPP-32), encoded by PPP1R1B (protein phosphatase 1, regulatory/inhibitor subunit 1B) gene, is enriched in neostriatal medium spiny neurons. It plays a key regulator role in dopaminergic and glutamatergic signaling pathways. The combined evidence from reduced DARPP-32 expression in the dorsolateral prefrontal cortex (DLPFC) in schizophrenic patients and from abnormalities in mice with a genetic deletion of DARPP-32 or with point mutations in phosphorylation sites of DARPP-32 suggested that it would be worthwhile to investigate the association between DARPP-32 and schizophrenia. In the present study, we genotyped five single nucleotide polymorphisms (SNPs) in the PPP1R1B gene and conducted a case-control study involving 520 schizophrenic patients and 386 healthy subjects drawn from the Chinese population. No allelic, genotypic or haplotypic association was found. However, our results do not preclude the possibility that the PPP1R1B is a susceptibility gene for schizophrenia in the Chinese population, since, as a central molecular switch, PPP1R1B may contribute to schizophrenia by interacting with other genes. Further functional analysis and genetic association studies are needed to determine the potential roles of PPP1R1B and other related genes in the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 69 | Psychiatr. Genet. 2008 Dec 18: 282-8 |
| PMID | 19018233 |
| Title | Phosphodiesterase-4A expression is reduced in cerebella of patients with bipolar disorder. |
| Abstract | The CAMP-specific phosphodiesterase-4 (PDE4) gene family has four members (PDE4 A, B, C, and D) and is the target of several potential therapeutic inhibitors. Recently, PDE4A5 has been shown to bind with disrupted in schizophrenia 1 (DISC1), which has been identified as a risk factor for schizophrenia, bipolar disorder, and major depression. We sought to examine whether PDE4A5 expression was altered in cerebella of patients with schizophrenia, bipolar disorder, and major depression. We measured protein levels of PDE4A isoforms in cerebella of patients with schizophrenia, bipolar disorder, and major depression versus matched controls using sodium dodecyl sulfate polyacrylamide gel electrophoresis and western blotting. We observed that specific isoforms of PDE4A were reduced in cerebella of patients with bipolar disorder, whereas there was no change in patients with schizophrenia or major depression. Our results are the first to show that PDE4A expression is altered in patients with bipolar disorder and provide potential new therapeutic avenues for treatment of this disorder. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 70 | Biochem. Biophys. Res. Commun. 2008 Dec 377: 1091-6 |
| PMID | 18983980 |
| Title | DISC1, PDE4B, and NDE1 at the centrosome and synapse. |
| Abstract | Disrupted-In-schizophrenia 1 (DISC1) is a risk factor for schizophrenia and other major mental illnesses. Its protein binding partners include the Nuclear Distribution Factor E Homologs (NDE1 and NDEL1), LIS1, and phosphodiesterases 4B and 4D (PDE4B and PDE4D). We demonstrate that NDE1, NDEL1 and LIS1, together with their binding partner dynein, associate with DISC1, PDE4B and PDE4D within the cell, and provide evidence that this complex is present at the centrosome. LIS1 and NDEL1 have been previously suggested to be synaptic, and we now demonstrate localisation of DISC1, NDE1, and PDE4B at synapses in cultured neurons. NDE1 is phosphorylated by CAMP-dependant Protein Kinase A (PKA), whose activity is, in turn, regulated by the CAMP hydrolysis activity of phosphodiesterases, including PDE4. We propose that DISC1 acts as an assembly scaffold for all of these proteins and that the NDE1/NDEL1/LIS1/dynein complex is modulated by CAMP levels via PKA and PDE4. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 71 | Pharmacol. Res. 2008 Apr 57: 296-302 |
| PMID | 18406625 |
| Title | Reduced activation of intracellular signaling pathways in rat prefrontal cortex after chronic phencyclidine administration. |
| Abstract | Evidence exists that schizophrenia is characterized by deficits in cell-cell communication and information processing. In the present study, we used the phencyclidine (PCP) animal model of schizophrenia to investigate possible defects in intracellular signaling proteins involved in neuroplasticity. Western Blot analysis has been performed to determine total and phospho-protein levels of extracellular signal-regulated kinases 1/2 (ERK1/2), type II calcium/calmodulin-dependent protein kinase (alphaCaMKII) and CAMP-response element binding protein (CREB) in prefrontal cortex (PFC) and hippoCAMPus (HIP) of rat chronically treated with PCP, whereas their mRNA levels were determined by real time RT-PCR. We found reduced levels of P-ERK1/2, P-alphaCaMKII and P-CREB in prefrontal cortex of PCP-treated animals when compared to controls, whereas no effects were observed on total protein or mRNA levels. Conversely, no significant changes were detected on protein levels or mRNA expression in hippoCAMPus. Given the role of ERK1/2, alphaCaMKII and CREB in neuroplastic mechanisms and cell communication, our data suggest that their decreased activation following chronic PCP administration can contribute to cortical defects occurring in schizophrenia, and may therefore represent potential targets for pharmacological intervention. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 72 | Schizophr. Res. 2008 Apr 101: 36-49 |
| PMID | 18394866 |
| Title | PDE4B polymorphisms and decreased PDE4B expression are associated with schizophrenia. |
| Abstract | schizophrenia has a complex genetic underpinning and variations in a number of candidate genes have been identified that confer risk of developing the disorder. We report in the present studies that several single nucleotide polymorphisms (SNPs) and a two-SNP haplotype in PDE4B are associated with an increased incidence of schizophrenia in two large populations of Caucasian and African American patients. The SNPs in PDE4B associated with schizophrenia occur in intronic sequences in the vicinity of a critical splice junction that gives rise to the expression of PDE4B isoforms with distinct regulation and function. We also observed specific decreases in phosphodiesterase 4B (PDE4B) isoforms in brain tissue obtained postmortem from patients diagnosed with schizophrenia and bipolar disorder. PDE4B metabolically inactivates the second messenger CAMP to regulate intracellular signaling in neurons throughout the brain. Thus, the present observations suggest that dysregulation of intracellular signaling mediated by PDE4B is a significant factor in the cause and expression, respectively, of schizophrenia and bipolar disorder and that targeting PDE4B-regulated signaling pathways may yield new therapies to treat the totality of these disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 73 | CNS Drugs 2008 -1 22: 983-93 |
| PMID | 18998737 |
| Title | The role of phosphodiesterases in schizophrenia : therapeutic implications. |
| Abstract | Recent studies have suggested that currently available antipsychotic medications, while useful in treating some aspects of schizophrenia, still possess considerable limitations. Improving the treatment of negative symptoms and cognitive dysfunction, and decreasing adverse effects remain significant challenges. Many new drug strategies have been proposed in recent years and increasing evidence suggests that members of the phosphodiesterase (PDE) gene family may play a role in the aetiology or treatment of schizophrenia. PDEs are key enzymes responsible for the degradation of the second messengers CAMP (3',5'-cyclic adenosine monophosphate) and cGMP (3',5'-cyclic guanosine monophosphate). Mammalian PDEs are composed of 21 genes and are categorized into 11 families based on sequence homology, enzymatic properties and sensitivity to pharmacological inhibitors. Representatives from most families have been identified in the brain by the presence of protein or RNA, and numerous studies suggest that PDEs play an important role in the regulation of intracellular signalling downstream of receptor activation in neurons. Insights into the multiple brain processes to which PDEs contribute are emerging from the phenotype of genetically engineered mice that lack activity of specific PDEs (knockout mice), as well as from in vitro and in vivo studies with PDE inhibitors.This article provides a brief overview of recent studies implicating PDE inhibition, focusing on PDE4 and PDE10, as targets for treating the positive, negative or cognitive symptoms associated with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 74 | Eur. J. Pharmacol. 2008 Nov 597: 27-33 |
| PMID | 18831971 |
| Title | Characterization of aripiprazole partial agonist activity at human dopamine D3 receptors. |
| Abstract | Aripiprazole is the first dopamine D2/D3 receptor partial agonist approved for use in the treatment of psychiatric disorders, including schizophrenia, bipolar disorder, and unipolar depression in the US. To explore the functional activity of aripiprazole at dopamine D3 receptors, we established Chinese hamster ovary (CHO) cell lines stably expressing high and low densities of Ser-9 and Gly-9 variants of human dopamine D3 receptors and compared aripiprazole's dopamine D3 pharmacological properties with other marketed and non-approved dopamine D3 receptor modulating agents on inhibition of forskolin-stimulated CAMP accumulation. Maximal cell responses for dopamine were dependent on receptor expression levels, and all cells had similar potency for dopamine responses. Aripiprazole, terguride, bifeprunox, OPC-4392 (7-(3-[4-(2,3-dimethylphenyl)piperazinyl]propoxy)-2(1H)-quinolinone), (-)-3-PPP ((-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine), SDZ 208-912 (N-[(8 alpha)-2-chloro-6-methylergolin-8-yl]-2,2-dimethylpropanamide), BP897 (N-[4-[4-(2-Methoxyphenyl)-1-piperazinyl]butyl]naphthalene-2-carboxamide) and GR103691 (4'-Acetyl-N-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]biphenyl-4-carboxamide) behaved as partial agonists. Aripiprazole's intrinsic activity was similar to that of BP897 and GR103691, lower than that of terguride, bifeprunox, OPC-4392, and (-)-3-PPP, and higher than that of SDZ 208-912. The Gly-9 variant did not differ from the Ser-9 variant with respect to those agonist potencies and intrinsic activities. These compounds blocked the action of dopamine with a maximum effect equal to that of each compound alone. ACR16 (4-(3-Methanesulfonyl-phenyl)-1-propyl-piperidine), quetiapine, clozapine, olanzapine, ziprasidone, risperidone, and haloperidol acted as antagonists. Aripiprazole's unique activity at dopamine D3 receptors may translate into clinically relevant outcomes in patients with a variety of neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 75 | Proc. Natl. Acad. Sci. U.S.A. 2008 Sep 105: 13656-61 |
| PMID | 18768802 |
| Title | Antagonism of dopamine D2 receptor/beta-arrestin 2 interaction is a common property of clinically effective antipsychotics. |
| Abstract | Since the unexpected discovery of the antipsychotic activity of chlorpromazine, a variety of therapeutic agents have been developed for the treatment of schizophrenia. Despite differences in their activities at various neurotransmitter systems, all clinically effective antipsychotics share the ability to interact with D2 class dopamine receptors (D2R). D2R mediate their physiological effects via both G protein-dependent and independent (beta-arrestin 2-dependent) signaling, but the role of these D2R-mediated signaling events in the actions of antipsychotics remains unclear. We demonstrate here that while different classes of antipsychotics have complex pharmacological profiles at G protein-dependent D2R long isoform (D2(L)R) signaling, they share the common property of antagonizing dopamine-mediated interaction of D2(L)R with beta-arrestin 2. Using two cellular assays based on a bioluminescence resonance energy transfer (BRET) approach, we demonstrate that a series of antipsychotics including haloperidol, clozapine, aripiprazole, chlorpromazine, quetiapine, olanzapine, risperidone, and ziprasidone all potently antagonize the beta-arrestin 2 recruitment to D2(L)R induced by quinpirole. However, these antipsychotics have various effects on D2(L)R mediated G(i/o) protein activation ranging from inverse to partial agonists and antagonists with highly variable efficacies and potencies at quinpirole-induced CAMP inhibition. These results suggest that the different classes of clinically effective antipsychotics share a common molecular mechanism involving inhibition of D2(L)R/beta-arrestin 2 mediated signaling. Thus, selective targeting of D2(L)R/beta-arrestin 2 interaction and related signaling pathways may provide new opportunities for antipsychotic development. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 76 | J. Pharmacol. Exp. Ther. 2008 Dec 327: 827-39 |
| PMID | 18753411 |
| Title | ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone]: a novel metabotropic glutamate receptor 5-selective positive allosteric modulator with preclinical antipsychotic-like and procognitive activities. |
| Abstract | Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) enhance N-methyl-d-aspartate receptor function and may represent a novel approach for the treatment of schizophrenia. ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone], a recently identified potent and selective mGlu5 PAM, increased (9-fold) the response to threshold concentration of glutamate (50 nM) in fluorometric Ca(2+) assays (EC(50) = 170 nM) in human embryonic kidney 293 cells expressing rat mGlu5. In the same system, ADX47273 dose-dependently shifted mGlu5 receptor glutamate response curve to the left (9-fold at 1 microM) and competed for binding of [(3)H]2-methyl-6-(phenylethynyl)pyridine (K(i) = 4.3 microM), but not [(3)H]quisqualate. In vivo, ADX47273 increased extracellular signal-regulated kinase and CAMP-responsive element-binding protein phosphorylation in hippoCAMPus and prefrontal cortex, both of which are critical for glutamate-mediated signal transduction mechanisms. In models sensitive to antipsychotic drug treatment, ADX47273 reduced rat-conditioned avoidance responding [minimal effective dose (MED) = 30 mg/kg i.p.] and decreased mouse apomorphine-induced climbing (MED = 100 mg/kg i.p.), with little effect on stereotypy or catalepsy. Furthermore, ADX47273 blocked phencyclidine, apomorphine, and amphetamine-induced locomotor activities (MED = 100 mg/kg i.p.) in mice and decreased extracellular levels of dopamine in the nucleus accumbens, but not in the striatum, in rats. In cognition models, ADX47273 increased novel object recognition (MED = 1 mg/kg i.p.) and reduced impulsivity in the five-choice serial reaction time test (MED = 10 mg/kg i.p.) in rats. Taken together, these effects are consistent with the hypothesis that allosteric potentiation of mGlu5 may provide a novel approach for development of antipsychotic and procognitive agents. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 77 | Learn. Mem. 2008 Aug 15: 551-64 |
| PMID | 18685145 |
| Title | Molecular mechanisms of stress-induced prefrontal cortical impairment: implications for mental illness. |
| Abstract | The symptoms of mental illness often involve weakened regulation of thought, emotion, and behavior by the prefrontal cortex. Exposure to stress exacerbates symptoms of mental illness and causes marked prefrontal cortical dysfunction. Studies in animals have revealed the intracellular signaling pathways activated by stress exposure that induce profound prefrontal cortical impairment: Excessive dopamine stimulation of D1 receptors impairs prefrontal function via CAMP intracellular signaling, leading to disconnection of prefrontal networks, while excessive norepinephrine stimulation of alpha1 receptors impairs prefrontal function via phosphatidylinositol-protein kinase C intracellular signaling. Genetic studies indicate that the genes disrupted in serious mental illness (bipolar disorder and schizophrenia) often encode for the intracellular proteins that serve as brakes on the intracellular stress pathways. For example, disrupted in schizophrenia 1 (DISC1) normally regulates CAMP levels, while regulator of G protein signaling 4 (RGS4) and diacylglycerol kinase (DGKH)-the molecule most associated with bipolar disorder- normally serve to inhibit phosphatidylinositol-protein kinase C intracellular signaling. Patients with mutations resulting in loss of adequate function of these genes likely have weaker endogenous regulation of these stress pathways. This may account for the vulnerability to stress and the severe loss of PFC regulation of behavior, thought, and affect in these illnesses. This review highlights the signaling pathways onto which genetic vulnerability and stress converge to impair PFC function and induce debilitating symptoms such as thought disorder, disinhibition, and impaired working memory. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 78 | J. Neurosci. Res. 2008 Nov 86: 3435-46 |
| PMID | 18627029 |
| Title | Cloning, expression, and functional analysis of rhesus monkey trace amine-associated receptor 6: evidence for lack of monoaminergic association. |
| Abstract | Several recent studies report an association between trace amine-associated receptor 6 (TAAR6) and susceptibility to schizophrenia and bipolar affective disorder in humans. However, endogenous TAAR6 agonists and the receptor signaling profile and brain distribution remain unclear. Here, we clone TAAR6 from the rhesus monkey and use transfected cells to investigate whether this receptor interacts with brain monoamines and a psychostimulant drug to trigger CAMP signaling or extracellular signal-regulated kinase (ERK) phosphorylation, while investigating its expression profile in the rhesus monkey brain. Unlike TAAR1, rhesus monkey TAAR6 did not alter CAMP levels in response to 10 microM of monoamines (dopamine, norepinephrine, serotonin, beta-phenylethylamine (beta-PEA), octopamine, tryptamine, and tyramine) or methamphetamine in stably transfected cells in vitro. Real-time cell electronic sensing analysis indicated that the receptor did not alter cell impedance or change the effect of forskolin on cell impedance at exposure to 20 microM of each monoamine, suggesting a lack of either Gs or Gi-linked signaling. Whereas kappa opioid receptor activation led to ERK phosphorylation at exposure to 1 microM U69593, rhesus monkey TAAR6 had no such effect at exposure to 10 microM of monoamines or methamphetamine. Membrane and cell surface localization of TAAR6 was confirmed by immunocytochemistry, biotinylation, and Western blot testing with a TAAR6 antibody in the transfected cells. Real-time reverse transcriptase-polymerase chain reaction amplification showed that TAAR6 mRNA was undetectable in selected rhesus monkey brain regions. Together, the data reveal that TAAR6 is unresponsive to brain monoamines and is not expressed in rhesus monkey brain monoaminergic nuclei, suggesting TAAR6 lacks direct association with brain monoaminergic neuronal function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 79 | Schizophr. Res. 2008 Aug 103: 192-200 |
| PMID | 18573638 |
| Title | Reduced prefrontal cortex DARPP-32 mRNA in completed suicide victims with schizophrenia. |
| Abstract | Dopamine-and-CAMP-regulated neuronal phosphoprotein (32 kDa) (DARPP-32), encoded by PPP1R1B, is expressed in brain regions receiving dopaminergic projections, including the prefrontal cortex (PFC), and is implicated in the pathophysiology of schizophrenia. The broad functional capacity of DARPP-32 has potential relevance to both psychotic and negative symptoms of schizophrenia. We wished to determine if DARPP-32 gene expression and variation at selected SNPs correlated significantly with patient phenotypes. We performed RT-PCR to quantify DARPP-32 mRNA from brain samples (Brodmann Area 46) donated by the Stanley Medical Research Institute (SMRI, Array Collection): 35 from unaffected controls (UC), 35 from patients with schizophrenia (SCZ), and 35 with bipolar disorder (BP). Relative mRNA expression was calculated in relation to the housekeeping gene Cyclophilin. SNP genotyping was conducted by PCR on DNA obtained from Brodmann Area 46. We found a significant difference in gene expression levels between SCZ patients who died by suicide (SCZ-S) (n=6) vs. other causes of death (SCZ-NS) (P<0.004), as well as between SCZ-S and UC (P<0.04). We genotyped the intron SNP rs907094 and found that the SCZ-S group was more similar to UC than to the SCZ-NS population. DARPP-32 expression differences between SCZ-S, SCZ-NS, and UC populations are consistent with previous literature suggesting that serotonin system components are also altered in suicide. Work in a larger sample is needed to confirm these findings. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 80 | Neuropharmacology 2008 Jun 54: 1215-22 |
| PMID | 18455202 |
| Title | Recruitment of beta-arrestin2 to the dopamine D2 receptor: insights into anti-psychotic and anti-parkinsonian drug receptor signaling. |
| Abstract | Drugs acting at dopamine D2-like receptors play a pivotal role in the treatment of both schizophrenia and Parkinson's disease. Recent studies have demonstrated a role for G-protein independent D2 receptor signaling pathways acting through beta-arrestin. In this study we describe the establishment of a Bioluminescence Resonance Energy Transfer (BRET) assay for measuring dopamine induced recruitment of human beta-arrestin2 to the human dopamine D2 receptor. Dopamine, as well as the dopamine receptor agonists pramipexole and quinpirole, acted as full agonists in the assay as reflected by their ability to elicit marked concentration dependent increases in the BRET signal signifying beta-arrestin2 recruitment to the D2 receptor. As expected from their effect on G-protein coupling and CAMP levels mediated through the D2 receptor RNPA, pergolide, apomorphine, ropinirole, bromocriptine, 3PPP, terguride, aripiprazole, SNPA all acted as partial agonists with decreasing efficacy in the BRET assay. In contrast, a wide selection of typical and atypical anti-psychotics was incapable of stimulating beta-arrestin2 recruitment to the D2 receptor. Moreover, we observed that haloperidol, sertindole, olanzapine, clozapine and ziprasidone all fully inhibited the dopamine induced beta-arrestin2 recruitment to D2 receptor (short variant) in a concentration dependent manner. We conclude that most anti-psychotics are incapable of stimulating beta-arrestin2 recruitment to the dopamine D2 receptor, in accordance with their antagonistic properties at the level of G-protein coupling. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 81 | J. Pharmacol. Exp. Ther. 2008 Jul 326: 230-9 |
| PMID | 18420599 |
| Title | Antipsychotic-like properties of phosphodiesterase 4 inhibitors: evaluation of 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (RO-20-1724) with auditory event-related potentials and prepulse inhibition of startle. |
| Abstract | Antipsychotic medications function through antagonism of D2 dopamine receptors. Blockade of D2 receptors causes an increase in intracellular CAMP, a ubiquitous second messenger. Inhibition of phosphodiesterase (PDE) activity, a family of enzymes that degrade cyclic nucleotides, causes the same effect. The conceptual linkage between dopamine D2 receptors and PDE activity via CAMP suggests a possible therapeutic potential for PDE inhibitors in schizophrenia. The limited number of studies in support of this hypothesis used rolipram, a specific inhibitor of the PDE4 family. In this study, we investigated the impact of 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (RO-20-1724), another PDE4-specific inhibitor, on auditory event-related potentials (ERPs), prepulse inhibition (PPI) of the startle reflex, and locomotor activity in mice. The ability to reverse amphetamine-induced alterations in ERPs and PPI was used as a model for psychosis. ERPs after RO-20-1724 revealed increased amplitude for the P20 and N40 ERP components. RO-20-1724 reversed the disruptive effect of amphetamines on ERPs and restored gating at a dose that did not impair locomotor activity. However, RO-20-1724 failed to reverse a amphetamine-induced decrease of PPI. Inconsistent results between these two psychosis models suggest that pure sensory processing, as measured with auditory ERPs, may be more sensitive to the effects of intracellular CAMP than sensorimotor effects as assessed with PPI. It remains unclear whether antipsychotic-like properties are a common feature of PDE4 inhibition, or if they are restricted to the pharmacological profile of rolipram. Future studies should examine how PDE4 subtype specificity might contribute to differences between rolipram and RO-20-1724 in sensorimotor gating. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 82 | Mol. Pharmacol. 2008 May 73: 1339-42 |
| PMID | 18314495 |
| Title | Messing up with traffic: different effects of antipsychotic agents on glutamate receptor complexes in vivo. |
| Abstract | Antipsychotic agents are major drugs for human neuropsychiatric conditions including schizophrenia, mood disorders, Tourette syndrome, and Alzheimer's disease. These drugs are divided in two groups-first-generation/typical and second-generation/atypical-on the basis of their propensity to induce extrapyramidal motor side effects. Furthermore, second-generation antipsychotics have been reported to be superior in addressing cognitive deficits in schizophrenia. Understanding differences between the mechanism of action of first- and second-generation antipsychotic agents thus represents an interesting opportunity for the development of new compounds having better therapeutic action and less side effects. In this issue of Molecular Pharmacology, Fumagalli et al. (p. 1484) report that long-term treatment with the first-generation drug haloperidol interferes with the trafficking of both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate glutamate receptor complexes and associated molecules post-synaptic densities 95 and Ca(2+)calmodulin-dependent protein kinase in the rat frontal cortex. In contrast, the second-generation drug olanzapine did not affect glutamate receptor trafficking. The action of haloperidol on glutamate receptor trafficking in specific brain regions may contribute to the low efficacy of this drug on cognitive deficits and to the development of side effects. Overall, antipsychotics have been shown to act upon multiple signaling mechanisms (e.g., CAMP-protein kinase A, betaArrestin 2-Akt-GSK-3, and phospholipase C-inositol-protein kinase C pathways), mostly by blocking D2-class dopamine receptors (first generation) or D2-class dopamine and 5-HT(2) serotonin receptors (second generation). Identification of specific pathways by which haloperidol affects glutamate receptor trafficking may thus represent an important next step toward the development of better antipsychotic drugs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 83 | J. Pharmacol. Exp. Ther. 2008 May 325: 681-90 |
| PMID | 18287214 |
| Title | Preclinical characterization of selective phosphodiesterase 10A inhibitors: a new therapeutic approach to the treatment of schizophrenia. |
| Abstract | We have recently proposed the hypothesis that inhibition of the cyclic nucleotide phosphodiesterase (PDE) 10A may represent a new pharmacological approach to the treatment of schizophrenia (Curr Opin Invest Drug 8:54-59, 2007). PDE10A is highly expressed in the medium spiny neurons of the mammalian striatum (Brain Res 985:113-126, 2003; J Histochem Cytochem 54:1205-1213, 2006; Neuroscience 139:597-607, 2006), where the enzyme is hypothesized to regulate both CAMP and cGMP signaling cascades to impact early signal processing in the corticostriatothalamic circuit (Neuropharmacology 51:374-385, 2006; Neuropharmacology 51:386-396, 2006). Our current understanding of the physiological role of PDE10A and the therapeutic utility of PDE10A inhibitors derives in part from studies with papaverine, the only pharmacological tool for this target extensively profiled to date. However, this agent has significant limitations in this regard, namely, relatively poor potency and selectivity and a very short exposure half-life after systemic administration. In the present report, we describe the discovery of a new class of PDE10A inhibitors exemplified by TP-10 (2-{4-[-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline succinic acid), an agent with greatly improved potency, selectivity, and pharmaceutical properties. These new pharmacological tools enabled studies that provide further evidence that inhibition of PDE10A represents an important new target for the treatment of schizophrenia and related disorders of basal ganglia function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 84 | J. Neurochem. 2008 Apr 105: 512-23 |
| PMID | 18194215 |
| Title | SP1 regulates a human SNAP-25 gene expression. |
| Abstract | The synaptosomal-associated protein of 25 kDa (SNAP-25) is a pre-synaptic plasma membrane protein. SNAP-25 plays an important role in synaptic vesicle membrane docking and fusion, which is involved in the regulation of neurotransmitter release. SNAP-25 has been implicated in the pathogenesis of neuropsychiatric disorders including schizophrenia, attention-deficit hyperactivity disorder and Alzheimer's disease. We cloned a 1584 bp segment of the 5' flanking region of the human SNAP-25 gene. A series of nested deletions of the 5' flanking region fragment were subcloned into the pGL3-basic luciferase reporter plasmid. N2A cells were transfected with the SNAP-25 promoter constructs and luciferase activity was measured as an indication of promoter activity. We identified a 188 bp fragment containing the transcription initiation site as the minimal region necessary for promoter activity. Several putative cis-acting elements including SP1, hypoxia inducible factor (HIF), CAMP-response element binding protein, T-cell factor/lymphocyte enhancer factor 1 (TCF/LEF1), AP1 and the signal transducer and activator of transcription-6 (STAT6) are found in the 5' flanking region of SNAP-25 gene. Transcriptional activation and gel shift assays showed that the human SNAP-25 gene promoter contains functional SP1 response elements. Over-expression of SP1 increased SNAP-25 gene expression and inhibition of SP1-mediated transcriptional activation reduced SNAP-25 gene expression. These results suggest that SP1 plays an important role in regulation of the human SNAP-25 gene expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 85 | Psychopharmacology (Berl.) 2008 Mar 197: 115-26 |
| PMID | 18060387 |
| Title | Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-4B (PDE4B) enzyme. |
| Abstract | Phosphodiesterases (PDEs) belonging to the PDE4 family control intracellular concentrations of cyclic adenosine monophosphate (CAMP) by catalyzing its hydrolysis. Four separate PDE4 genes (PDE4A, PDE4B, PDE4C, and PDE4D) have been identified. PDE4 has been reported to be involved in various central nervous system (CNS) functions including depression, memory, and schizophrenia, although the specific subtype mediating these effects remains unclear. To investigate the role of PDE4B in the CNS, PDE4B wild-type and knockout mice (C57BL/6N background) were assessed in a variety of well-characterized behavioral tasks, and their brains were assayed for monoamine content. Knockout mice showed a significant reduction in prepulse inhibition. Spontaneous locomotor activity was decreased (16%) in knockout mice. Furthermore, when challenged with amphetamine, both groups of mice responded similarly to a low dose of d-amphetamine (1.0 mg/kg), but knockout mice showed an enhanced response to a higher dose (1.78 mg/kg). Decreases in baseline levels of monoamines and their metabolites within the striatum of knockout mice were also observed. PDE4B knockout mice showed a modest decrease in immobility time in the forced swim test that approached significance. In several other tests, including the elevated plus maze, hot plate, passive avoidance, and Morris water maze, wild-type and knockout mice performed similarly. The present studies demonstrate decreased striatal DA and 5-HT activity in the PDE4B knockout mice associated with decreased prepulse inhibition, decreased baseline motor activity, and an exaggerated locomotor response to amphetamine. These data further support a role for PDE4B in psychiatric diseases and striatal function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 86 | Schizophr. Res. 2008 Mar 100: 334-41 |
| PMID | 18055181 |
| Title | Genetic analysis of the gene coding for DARPP-32 (PPP1R1B) in Japanese patients with schizophrenia or bipolar disorder. |
| Abstract | Several lines of evidence, including genome-wide linkage scans and postmortem brain studies of patients with schizophrenia or bipolar disorder, have suggested that DARPP-32 (dopamine- and CAMP-regulated phosphoprotein, 32 kDa), a key regulatory molecule in the dopaminergic signaling pathway, is involved in these disorders. After evaluating the linkage disequilibrium pattern of the gene encoding DARPP-32 (PPP1R1B; located on 17q12), we conducted association analyses of this gene with schizophrenia and bipolar disorder. Single-marker and haplotypic analyses of four single nucleotide polymorphisms (SNPs; rs879606, rs12601930, rs907094, and rs3764352) in a sample set (subjects with schizophrenia=384, subjects with bipolar disorder=318, control subjects=384) showed that PPP1R1B polymorphisms were not significantly associated with schizophrenia, whereas, even after Bonferroni corrections, significant associations with bipolar disorder were observed for rs12601930 (corrected genotypic p=0.00059) and rs907094 (corrected allelic p=0.040). We, however, could not confirm these results in a second independent sample set (subjects with bipolar disorder=366, control subjects=370). We now believe that the significant association observed with the first sample set was a result of copy number aberrations in the region surrounding these SNPs. Our findings suggest that PPP1R1B SNPs are unlikely to be related to the development of schizophrenia and bipolar disorder in the Japanese population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 87 | J. Neurochem. 2008 Mar 104: 1450-65 |
| PMID | 18028338 |
| Title | Cholecystokinin-2 receptor mediated gene expression in neuronal PC12 cells. |
| Abstract | Cholecystokinin (CCK) is abundantly expressed in the CNS, in which it regulates feeding behavior and long-term memory. Moreover, CCK has been implicated in mental disorders, such as anxiety and schizophrenia. Despite its manifest physiological and pathophysiological role, the molecular targets of neuronal CCK are incompletely understood. To identify genes regulated by neuronal CCK, we generated neuronal PC12 cells stably expressing the CCK-2 receptor (CCK-2R) and treated the cells with sulphated CCK-8 for 2-16 h, before the global expression profile was examined. The changes in gene expression peaked after 2 h, with 67 differentially expressed transcripts identified. A pathway analysis indicated that CCK was implicated in the regulation of the circadian clock system, the plasminogen system and cholesterol metabolism. But transcripts encoding proteins involved in dopamine signaling, ornithine decarboxylase (ODC) regulation, memory and epidermal growth factor receptor (EGFR) signaling were also found. Several target genes contained CAMP response elements (CREs), serum response elements (SREs), activator protein 1 (AP1) elements and GC-rich regions, but otherwise no common regulatory promoter element could be identified. Comparison with forskolin- and nerve growth factor (NGF)-treated PC12 cells showed that CCK induced a separate set of target genes. Taken together, we propose that neuronal CCK may have a role in the regulation of the circadian rhythm, the metabolism of cerebral cholesterol and in the regulation of the plasminogen system. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 88 | Mol. Psychiatry 2008 Jan 13: 36-64 |
| PMID | 17912248 |
| Title | The DISC locus in psychiatric illness. |
| Abstract | The DISC locus is located at the breakpoint of a balanced t(1;11) chromosomal translocation in a large and unique Scottish family. This translocation segregates in a highly statistically significant manner with a broad diagnosis of psychiatric illness, including schizophrenia, bipolar disorder and major depression, as well as with a narrow diagnosis of schizophrenia alone. Two novel genes were identified at this locus and due to the high prevalence of schizophrenia in this family, they were named Disrupted-in-schizophrenia-1 (DISC1) and Disrupted-in-schizophrenia-2 (DISC2). DISC1 encodes a novel multifunctional scaffold protein, whereas DISC2 is a putative noncoding RNA gene antisense to DISC1. A number of independent genetic linkage and association studies in diverse populations support the original linkage findings in the Scottish family and genetic evidence now implicates the DISC locus in susceptibility to schizophrenia, schizoaffective disorder, bipolar disorder and major depression as well as various cognitive traits. Despite this, with the exception of the t(1;11) translocation, robust evidence for a functional variant(s) is still lacking and genetic heterogeneity is likely. Of the two genes identified at this locus, DISC1 has been prioritized as the most probable candidate susceptibility gene for psychiatric illness, as its protein sequence is directly disrupted by the translocation. Much research has been undertaken in recent years to elucidate the biological functions of the DISC1 protein and to further our understanding of how it contributes to the pathogenesis of schizophrenia. These data are the main subject of this review; however, the potential involvement of DISC2 in the pathogenesis of psychiatric illness is also discussed. A detailed picture of DISC1 function is now emerging, which encompasses roles in neurodevelopment, cytoskeletal function and CAMP signalling, and several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 89 | Neurosci. Res. 2009 Sep 65: 53-63 |
| PMID | 19465068 |
| Title | Colocalization of dopamine receptor subtypes with dopamine and cAMP-regulated phosphoprotein (DARPP-32) in rat brain. |
| Abstract | In the present study using indirect immunofluorescence immunohistochemistry, co-immunoprecipitation and western blot analysis we determined the colocalization of dopamine receptors 1-5 and dopamine and CAMP-regulated phosphoprotein (DARPP-32) in rat brain cortex and striatum. All five DR subtypes and DARPP-32 were expressed in rat brain cortex and striatum. DARPP-32 positive neurons displayed comparative colocalization with DR1-5. In cingulate cortex, the colocalization of DR subtypes was greatly different from frontal or temporal cortex. D1R is one of the most predominant subtypes which colocalized with DARPP-32 in cortex as well as striatum and followed by D2R, D3R, D4R and D5R. Amongst all DR subtypes D5R was coexpressed the least with DARPP-32 positive neurons. Consistent with immunohistochemical data, western blot analysis also reveals comparable distribution of DR subtypes and DARPP-32 in cortex and striatum. Colocalization studies were also supported by using co-immunoprecipitate assay displaying DARPP-32 expression in DR immunoprecipitate from tissue lysate prepared from cortex and striatum. Taken together our data support receptor specific association of DARPP-32 with DR subtypes that might shed new information in drugs of abuse and pathophysiology of neurodegenerative diseases as well as neuropsychiatric disorders such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 90 | Behav. Brain Res. 2009 Sep 202: 179-83 |
| PMID | 19463699 |
| Title | The biological basis of anger: associations with the gene coding for DARPP-32 (PPP1R1B) and with amygdala volume. |
| Abstract | Recent findings have highlighted the importance of DARPP-32 (dopamine- and CAMP-regulated phosphoprotein, 32 kDa), a key regulatory molecule in the dopaminergic signalling pathway for dopamine related phenotypes like antisocial-behavior, drug addiction and schizophrenia. This is the first study investigating the role of the DARPP-32 gene for personality. In a sample of n=838 healthy German Caucasian subjects we found a significant association between rs907094 and ANGER. Carriers of the T-allele showed significantly higher ANGER scores than participants without a T-allele (F((1,837))=9.52, p=0.002). In a second step we validated self-report data of ANGER by investigating their relation to structural brain differences in anger-related brain regions using voxel-based morphometry. A negative association between ANGER scores and the volume of the left amygdala could be detected. The present findings yield genetic evidence for the importance of dopaminergic signal transduction for the personality trait of ANGER. In addition volumetric MRI data support the role of the amygdala for the processing of anger. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 91 | J. Pharmacol. Exp. Ther. 2009 Nov 331: 574-90 |
| PMID | 19661377 |
| Title | Phosphodiesterase 10A inhibitor activity in preclinical models of the positive, cognitive, and negative symptoms of schizophrenia. |
| Abstract | Following several recent reports that suggest that dual CAMP and cGMP phosphodiesterase 10A (PDE10A) inhibitors may present a novel mechanism to treat positive symptoms of schizophrenia, we sought to extend the preclinical characterization of two such compounds, papaverine [1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline] and MP-10 [2-{[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy]methyl}quinoline], in a variety of in vivo and in vitro assays. Both of these compounds were active in a range of antipsychotic models, antagonizing apomorphine-induced climbing in mice, inhibiting conditioned avoidance responding in both rats and mice, and blocking N-methyl-D-aspartate antagonist-induced deficits in prepulse inhibition of acoustic startle response in rats, while improving baseline sensory gating in mice, all of which strengthen previously reported observations. These compounds also demonstrated activity in several assays intended to probe negative symptoms and cognitive deficits, two disease domains that are underserved by current treatments, with both compounds showing an ability to increase sociality in BALB/cJ mice in the social approach/social avoidance assay, enhance social odor recognition in mice and, in the case of papaverine, improve novel object recognition in rats. Biochemical characterization of these compounds has shown that PDE10A inhibitors modulate both the dopamine D1-direct and D2-indirect striatal pathways and regulate the phosphorylation status of a panel of glutamate receptor subunits in the striatum. It is striking that PDE10A inhibition increased the phosphorylation of the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor GluR1 subunit at residue serine 845 at the cell surface. Together, our results suggest that PDE10A inhibitors alleviate both dopaminergic and glutamatergic dysfunction thought to underlie schizophrenia, which may contribute to the broad-spectrum efficacy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 92 | Behav. Brain Res. 2009 Dec 205: 96-101 |
| PMID | 19539658 |
| Title | Early postnatal depletion of NMDA receptor development affects behaviour and NMDA receptor expression until later adulthood in rats--a possible model for schizophrenia. |
| Abstract | There is increasing evidence that a dysfunction of the N-methyl-d-aspartate (NMDA) receptor system plays a key role in the pathophysiology of schizophrenia. Non-competitive NMDA-antagonists induce schizophrenia-like symptoms and cognitive impairment in healthy humans as well as rodents. As receptor dysfunction precedes clinical disorder manifestation, the present study investigated whether transient perinatal NMDA antagonism constitutes a suitable long-term animal model for schizophrenia. Male Wistar rats were treated from postnatal days 6-21 with the NMDA receptor antagonist MK-801, and then subjected to behavioural analysis up to an age of 180d. Alterations in cortical NMDA receptor expression and lymphocyte CAMP-response-element-binding-protein (CREB) were assessed. In comparison to controls, MK-801-treated animals showed differences in behaviour up to an age of 180d. Western blot analysis revealed that transient perinatal application of MK-801 caused a persistent increase in cortical NMDA-R1 protein in combination with a persistent disturbance of CREB phosphorylation, a downstream target of NMDA signalling. This animal model demonstrates that early postnatal NMDA receptor blockade leads to schizophrenia-like symptoms with persistent behavioural and neurochemical disturbances throughout life. Therefore, it might provide a basis for further understanding of the disease and evaluation of new therapeutic strategies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 93 | Eur. J. Pharmacol. 2009 Apr 607: 35-40 |
| PMID | 19217900 |
| Title | Receptor reserve-dependent properties of antipsychotics at human dopamine D2 receptors. |
| Abstract | Aripiprazole is the first dopamine D(2)/D(3) receptor partial agonist approved for use in the treatment of psychiatric disorders including schizophrenia, bipolar disorder, and unipolar depression in the US. Aripiprazole has demonstrated a relatively favorable side effect profile compared to other commonly prescribed antipsychotics, including a low propensity for treatment-limiting extrapyramidal symptoms, hyperprolactinemia, and body weight gain. In an effort to elucidate aripiprazole's pharmacological activity in relation to clinically relevant fluctuation of dopamine D(2) receptor reserves, we compared the properties of aripiprazole to other antipsychotics, quetiapine, clozapine, olanzapine, ziprasidone, risperidone and haloperidol, a dopamine D(2) receptor partial agonist, bifeprunox, dopamine D(3) receptor modulators, BP897 (N-[4-[4-(2-Methoxyphenyl)-1-piperazinyl]butyl]naphthalene-2-carboxamide) and GR103691 (4'-Acetyl-N-[4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl]biphenyl-4-carboxamide), and a 5-HT(1A) partial agonist, buspirone using forskolin-stimulated CAMP accumulation in clonal Chinese hamster ovary cell lines expressing low and high densities of human dopamine D(2S) receptors (hD(2S)-Low and hD(2S)-High, respectively). In hD(2S)-Low cells lacking receptor reserves for dopamine, all drugs antagonized dopamine responses, and their potencies correlated well with respective affinities. In hD(2S)-High cells possessing receptor reserves, all antipsychotics except aripiprazole antagonized dopamine responses, and their antagonist potencies were less than those in hD(2S)-Low cells treated with the equal dopamine concentration. In contrast, aripiprazole and bifeprunox acted as full agonists. BP897, GR103691 and buspirone acted as partial agonists. These data suggest that the level of receptor reserves influences antagonist potencies and side effects associated with antipsychotics. Aripiprazole's unique receptor reserve dependent properties may account for its favorable tolerability in the clinical setting. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 94 | Mol. Pharmacol. 2009 Apr 75: 991-1003 |
| PMID | 19164443 |
| Title | Regulation of group II metabotropic glutamate receptors by G protein-coupled receptor kinases: mGlu2 receptors are resistant to homologous desensitization. |
| Abstract | We examined the regulation of mGlu2 and mGlu3 metabotropic glutamate receptor signaling prompted by the emerging role of these receptor subtypes as therapeutic targets for psychiatric disorders, such as anxiety and schizophrenia. In transfected human embryonic kidney 293 cells, G-protein-coupled receptor kinase (GRK) 2 and GRK3 fully desensitized the agonist-dependent inhibition of CAMP formation mediated by mGlu3 receptors. In contrast, GRK2 or other GRKs did not desensitize the CAMP response to mGlu2 receptor activation. Desensitization of mGlu3 receptors by GRK2 required an intact kinase activity, as shown by the use of the kinase-dead mutant GRK2-K220R or the recombinant GRK2 C-terminal domain. Overexpression of beta-arrestin1 also desensitized mGlu3 receptors and did not affect the CAMP signaling mediated by mGlu2 receptors. The difference in the regulation of mGlu2 and mGlu3 receptors was signal-dependent because GRK2 desensitized the activation of the mitogen-activated protein kinase pathway mediated by both mGlu2 and mGlu3 receptors. In vivo studies confirmed the resistance of mGlu2 receptor-mediated CAMP signaling to homologous desensitization. Wild-type, mGlu2(-/-), or mGlu3(-/-) mice were treated intraperitoneally with saline or the mixed mGlu2/3 receptor agonist (-)-2-oxa-4-aminobicyclo[3.1.0]-exhane-4,6-dicarboxylic acid (LY379268; 1 mg/kg) once daily for 7 days. Inhibition of forskolin-stimulated CAMP formation by LY379268 was measured in cortical slices prepared 24 h after the last injection. Agonist pretreatment fully desensitized the CAMP response in wild-type and mGlu2(-/-) mice but had no effect in mGlu3(-/-) mice, in which LY379268 could only activate the mGlu2 receptor. We predict the lack of tolerance when mixed mGlu2/3 receptor agonists or selective mGlu2 enhancers are used continually in patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 95 | Am J Psychiatry 2009 Feb 166: 226-33 |
| PMID | 19074977 |
| Title | An odor-specific threshold deficit implicates abnormal intracellular cyclic AMP signaling in schizophrenia. |
| Abstract | Although olfactory deficits are common in schizophrenia, their underlying pathophysiology remains unknown. Recent evidence has suggested that CAMP signaling may be disrupted in schizophrenia. Since CAMP mediates signal transduction in olfactory receptor neurons, this could contribute to the etiology of observed olfactory deficits. This study was designed to test this hypothesis by determining odor detection threshold sensitivities to two odorants that differ in their relative activations of this intracellular CAMP signaling cascade. Thirty schizophrenia patients, 25 healthy comparison subjects, and 19 unaffected first-degree relatives of schizophrenia patients were studied. Odor detection threshold sensitivities were measured for the two odorants citralva and lyral. Although both have fruity/floral scents, citralva strongly activates adenylyl cyclase to increase CAMP levels, while lyral is a very weak activator of adenylyl cyclase. There was a significant group-by-odor interaction. Both schizophrenia patients and unaffected first-degree relatives were impaired in their ability to detect lyral versus citralva. Comparison subjects were equally sensitive to both odorants. This selective deficit could not be explained by differences in age, sex, smoking, clinical symptom profile, or medication use. This study establishes the presence of an odor-specific hyposmia that may denote a disruption of CAMP-mediated signal transduction in schizophrenia. The presence of a parallel deficit in the patients' unaffected first-degree relatives suggests that this deficit is genetically mediated. Although additional physiological studies are needed to confirm the underlying mechanism, these results offer strong inferential support for the hypothesis that CAMP signaling is dysregulated in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 96 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2009 Mar 33: 214-9 |
| PMID | 19059449 |
| Title | The leukocytes expressing DARPP-32 are reduced in patients with schizophrenia and bipolar disorder. |
| Abstract | Bipolar disorder (BPD) and schizophrenia (SCZ) are severe disorders representing an enormous social, familiar and individual burden, being SCZ the most disabling psychiatric disorder characterized by psychosis and cognitive impairment. It is well known that SCZ and BPD are associated with abnormalities in dopamine signaling pathway. Recent data in the literature have demonstrated altered expression levels of some proteins involved in the modulation of this pathway in both brain and peripheral tissues. It was shown that protein and mRNA levels of dopamine and CAMP regulated phosphoprotein (DARPP-32) were downregulated in dorsolateral prefrontal cortex (DLPFC) of patients with SCZ or BPD when compared to controls. Due to the difficulty to access brain tissue and the absence of objective laboratory tests for bio-markers, we measured DARPP-32 expression in blood cell sub-populations (CD4+ T lymphocytes, CD56+ NK cells, CD19+ B lymphocytes and CD14+ monocytes) taking advantage of the close relation of nervous and immune systems. Using flow cytometry as the analytical method, our results have shown that the DARPP-32 expression was diminished in CD4+ T lymphocytes, CD19+ B lymphocytes and CD14+ monocytes of BPD patients and was also decreased in CD4+ T lymphocytes and CD56+ NK cells of SCZ patients. These results showed that DARPP-32 expression in immune cells agrees with reports of reduced DARPP-32 protein in the DLPFC of BPD or SCZ patients. Our data suggest that DARPP-32 expression in PBMC could be used as a source of bio-markers to help in the treatment response of neuropsychiatry disorders as a window to the changes in the brain of those patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 97 | Mol. Psychiatry 2009 Apr 14: 398-415, 347 |
| PMID | 19030002 |
| Title | Developmental etiology for neuroanatomical and cognitive deficits in mice overexpressing Galphas, a G-protein subunit genetically linked to schizophrenia. |
| Abstract | schizophrenia is a widespread psychiatric disorder, affecting 1% of people. Despite this high prevalence, schizophrenia is not well treated because of its enigmatic developmental origin. We explore here the developmental etiology of endophenotypes associated with schizophrenia using a regulated transgenic approach in mice. Recently, a polymorphism that increases mRNA levels of the G-protein subunit Galphas was genetically linked to schizophrenia. Here we show that regulated overexpression of Galphas mRNA in forebrain neurons of mice is sufficient to cause a number of schizophrenia-related phenotypes, as measured in adult mice, including sensorimotor gating deficits (prepulse inhibition of acoustic startle, PPI) that are reversed by haloperidol or the phosphodiesterase inhibitor rolipram, psychomotor agitation (hyperlocomotion), hippoCAMPus-dependent learning and memory retrieval impairments (hidden water maze, contextual fear conditioning), and enlarged ventricles. Interestingly, overexpression of Galphas during development plays a significant role in some (PPI, spatial learning and memory and neuroanatomical deficits) but not all of these adulthood phenotypes. Pharmacological and biochemical studies suggest the Galphas-induced behavioral deficits correlate with compensatory decreases in hippoCAMPal and cortical cyclic AMP (CAMP) levels. These decreases in CAMP may lead to reduced activation of the guanine exchange factor Epac (also known as RapGEF 3/4) as stimulation of Epac with the select agonist 8-pCPT-2'-O-Me-CAMP increases PPI and improves memory in C57BL/6J mice. Thus, we suggest that the developmental impact of a given biochemical insult, such as increased Galphas expression, is phenotype specific and that Epac may prove to be a novel therapeutic target for the treatment of both developmentally regulated and non-developmentally regulated symptoms associated with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 98 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009 Jun 150B: 527-34 |
| PMID | 18785206 |
| Title | Gene expression and association analyses of the phosphodiesterase 4B (PDE4B) gene in major depressive disorder in the Japanese population. |
| Abstract | The phosphodiesterase 4B (PDE4B) interacts with disrupted-in-schizophrenia 1 (DISC1), which is a known genetic risk factor for schizophrenia, bipolar disorder and major depressive disorder (MDD). PDE4B is also important in the regulation of CAMP signaling, a second messenger implicated in learning, memory, and mood. In this study, we determined mRNA expression levels of the PDE4B gene in the peripheral blood leukocytes of patients with MDD and control subjects (n = 33, each). Next we performed two-stage case-controlled association analyses (first set; case = 174, controls = 348; second set; case = 481, controls = 812) in the Japanese population to determine if the PDE4B gene is implicated in MDD. In the leukocytes, a significantly higher expression of the PDE4B mRNA was observed in the drug-naïve MDD patients compared with control subjects (P < 0.0001) and the expression of the MDD patients significantly decreased after antidepressant treatment (P = 0.030). In the association analysis, we observed significant allelic associations of four SNPs (the most significant, rs472952; P = 0.002) and a significant haplotypic association (permutation P = 0.019) between the PDE4B gene and MDD in the first-set samples. However, we could not confirm these significant associations in the following independent second-set of samples. Our results suggest that the PDE4B gene itself does not link to MDD but the elevated mRNA levels of PDE4B might be implicated in the pathophysiology of MDD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 99 | Psychopharmacology (Berl.) 2009 Jan 202: 419-43 |
| PMID | 18709359 |
| Title | Selective phosphodiesterase inhibitors: a promising target for cognition enhancement. |
| Abstract | One of the major complaints most people face during aging is an impairment in cognitive functioning. This has a negative impact on the quality of daily life and is even more prominent in patients suffering from neurodegenerative and psychiatric disorders including Alzheimer's disease, schizophrenia, and depression. So far, the majority of cognition enhancers are generally targeting one particular neurotransmitter system. However, recently phosphodiesterases (PDEs) have gained increased attention as a potential new target for cognition enhancement. Inhibition of PDEs increases the intracellular availability of the second messengers cGMP and/or CAMP. The aim of this review was to provide an overview of the effects of phosphodiesterase inhibitors (PDE-Is) on cognition, the possible underlying mechanisms, and the relationship to current theories about memory formation. Studies of the effects of inhibitors of different PDE families (2, 4, 5, 9, and 10) on cognition were reviewed. In addition, studies related to PDE-Is and blood flow, emotional arousal, and long-term potentiation (LTP) were described. PDE-Is have a positive effect on several aspects of cognition, including information processing, attention, memory, and executive functioning. At present, these data are likely to be explained in terms of an LTP-related mechanism of action. PDE-Is are a promising target for cognition enhancement; the most suitable candidates appear to be PDE2-Is or PDE9-Is. The future for PDE-Is as cognition enhancers lies in the development of isoform-specific PDE-Is that have limited aversive side effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 100 | Cardiovasc Psychiatry Neurol 2009 -1 2009: 618586 |
| PMID | 20037658 |
| Title | Pharmacological Characterization of Inositol 1,4,5-tris Phosphate Receptors in Human Platelet Membranes. |
| Abstract | The phosphatidylinositol (PI) hydrolysis signaling system has been shown to be altered in platelets of depressed and schizophrenic subjects. Inositol (1,4,5) trisphosphate (Ins(1,4,5)P(3)), an integral component of the PI signaling system, mobilizes Ca(2+) by activating Ins(1,4,5)P(3) receptors. To eventually investigate the role of Ins(1,4,5)P(3) receptors in depression and other mental disorders, we characterized [(3)H]Ins(1,4,5)P(3) binding sites in crude platelet membranes prepared from small amounts of blood obtained from healthy human control subjects. We found a single, saturable binding site for [(3)H]Ins(1,4,5)P(3) to crude platelet membranes, which is time dependent and modulated by pH, inositol phosphates, and heparin. Since cyclic adenosine monophosphate (CAMP) and Ca(2+) have been shown to be important modulators in Ins(1,4,5)P(3) receptors, in the present study we also determined the effects of various concentrations of CaCI(2) and forskolin on Ins(1,4,5)P(3) binding to platelet membranes. CaCI(2) modulated [(3)H]Ins(1,4,5)P(3) binding sites in a biphasic manner: at lower concentrations it inhibited [(3)H]Ins(1,4,5)P(3) binding, whereas at higher concentrations, it stimulated [(3)H]Ins(1,4,5)P(3) binding. On the other hand, forskolin inhibited [(3)H]Ins(1,4,5)P(3) binding. Our results thus suggest that the pharmacological characteristics of [(3)H]Ins(1,4,5)P(3) binding to crude platelet membranes are similar to that of Ins(1,4,5)P(3) receptors; and that both Ca(2+) and CAMP modulate [(3)H]Ins(1,4,5)P(3) binding in crude platelet membranes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 101 | Curr Top Behav Neurosci 2010 -1 4: 629-56 |
| PMID | 21312416 |
| Title | Molecules, signaling, and schizophrenia. |
| Abstract | schizophrenia is one of the most common psychiatric disorders, but despite some progress in identifying the genetic factors implicated in its development, the molecular mechanisms underlying its etiology and pathogenesis remain poorly understood. However, accumulating evidence suggests that regardless of the underlying genetic complexity, the mechanisms of the disease may impact a small number of common signaling pathways. In this review, we discuss the evidence for a role of schizophrenia susceptibility genes in intracellular signaling cascades by focusing on three prominent candidate genes: AKT, PPP3CC (calcineurin), and DISC1. We describe the regulation of a number of signaling cascades by AKT and calcineurin through protein phosphorylation and dephosphorylation, and the recently uncovered functions of DISC1 in CAMP and GSK3beta signaling. In addition, we present independent evidence for the involvement of their downstream signaling pathways in schizophrenia. Finally, we discuss evidence supporting an impact of these susceptibility genes on common intracellular signaling pathways and the convergence of their effects on neuronal processes implicated in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 102 | J. Med. Chem. 2010 Jun 53: 4399-411 |
| PMID | 20450197 |
| Title | Discovery of imidazo[1,5-a]pyrido[3,2-e]pyrazines as a new class of phosphodiesterase 10A inhibitiors. |
| Abstract | Novel imidazo[1,5-a]pyrido[3,2-e]pyrazines have been synthesized and characterized as both potent and selective phosphodiesterase 10A (PDE10A) inhibitors. For in vitro characterization, inhibition of PDE10A mediated CAMP hydrolysis was used and a QSAR model was established to analyze substitution effects. The outcome of this analysis was complemented by the crystal structure of PDE10A in complex with compound 49. Qualitatively new interactions between inhibitor and binding site were found, contrasting with previously published crystal structures of papaverine-like inhibitors. In accordance with the known antipsychotic potential of PDE10A inhibitors, MK-801 induced stereotypy and hyperactivity in rats were reversed by selected compounds. Thus, a promising compound class has been identified for the treatment of schizophrenia that could circumvent side effects connected with current therapies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 103 | Synapse 2010 Jul 64: 550-5 |
| PMID | 20222156 |
| Title | Levels of phosphodiesterase 4A and 4B are altered by chronic treatment with psychotropic medications in rat frontal cortex. |
| Abstract | Our laboratory has recently demonstrated altered expression of phosphodiesterase (PDE) 4A and 4B in subjects with autism, bipolar disorder, and schizophrenia, suggesting disrupted CAMP signaling in these diagnostic groups. In the current study, we measured expression of PDEs in rat frontal cortex (FC) following chronic treatment with clozapine, fluoxetine, haloperidol, lithium, olanzapine, valproic acid (VPA), or sterile saline for 21 days. Western blotting experiments showed decreased expression of PDE4A subtypes in FC following treatment with clozapine, haloperidol, lithium, and VPA. PDE4B subtypes were similarly reduced in FC following treatment with clozapine, fluoxetine, and lithium. We also measured levels of nine PDE subtypes via qRT-PCR in FC and found significant upregulation of PDE1A and PDE8B following treatment with olanzapine, while treatment with lithium reduced expression of mRNA for PDE8B. Our results demonstrate altered expression of PDE4A and PDE4B in response to a variety of psychotropic medications suggesting potentially new therapeutic avenues for treatment of neuropsychiatric diseases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 104 | Nat. Biotechnol. 2010 Jan 28: 63-70 |
| PMID | 20037581 |
| Title | Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. |
| Abstract | Phosphodiesterase 4 (PDE4), the primary CAMP-hydrolyzing enzyme in cells, is a promising drug target for a wide range of conditions. Here we present seven co-crystal structures of PDE4 and bound inhibitors that show the regulatory domain closed across the active site, thereby revealing the structural basis of PDE4 regulation. This structural insight, together with supporting mutagenesis and kinetic studies, allowed us to design small-molecule allosteric modulators of PDE4D that do not completely inhibit enzymatic activity (I(max) approximately 80-90%). These allosteric modulators have reduced potential to cause emesis, a dose-limiting side effect of existing active site-directed PDE4 inhibitors, while maintaining biological activity in cellular and in vivo models. Our results may facilitate the design of CNS therapeutics modulating CAMP signaling for the treatment of Alzheimer's disease, Huntington's disease, schizophrenia and depression, where brain distribution is desired for therapeutic benefit. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 105 | Trends Biochem. Sci. 2010 Feb 35: 91-100 |
| PMID | 19864144 |
| Title | Underpinning compartmentalised cAMP signalling through targeted cAMP breakdown. |
| Abstract | It is becoming increasingly apparent that spatial regulation of cell signalling processes is critical to normal cellular function. In this regard, CAMP signalling regulates many pivotal cellular processes and has provided the paradigm for signal compartmentalization. Recent advances show that isoforms of the CAMP-degrading phosphodiesterase-4 (PDE4) family are targeted to discrete signalling complexes. There they sculpt local CAMP gradients that can be detected by genetically encoded CAMP sensors, and gate the activation of spatially localized signalling through sequestered PKA and EPAC sub-populations. Genes for these important regulatory enzymes are linked to schizophrenia, stroke and asthma, thus indicating the therapeutic potential that selective inhibitors could have as anti-inflammatory, anti-depressant and cognitive enhancer agents. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 106 | Neuropharmacology 2010 Feb 58: 444-51 |
| PMID | 19765598 |
| Title | Alterations in gene regulation following inhibition of the striatum-enriched phosphodiesterase, PDE10A. |
| Abstract | PDE10A is a member of the phosphodiesterase superfamily highly enriched within medium spiny neurons (MSN) in mammalian striatum. We have used inhibitors of PDE10A and quantitative measures of mRNA to demonstrate that PDE10A controls striatal gene expression by regulating MSN cyclic nucleotide signaling pathways. Acute treatment with PDE10A inhibitors produces rapid and transient transcription of the immediate early gene cfos in rat striatum. Although inhibition of PDE10A causes accumulation of both CAMP and cGMP, the increase in striatal cfos expression appears to depend on changes in CAMP, since the increase is present in mice deficient in nNOS which fail to increase cGMP in response to PDE10A inhibition. Consistent with its expression in a majority of striatal MSN, PDE10A inhibition significantly induces expression of both substance P and enkephalin, neuropeptide markers for the direct and indirect striatal output pathways, respectively. These findings support the hypothesis that PDE10A modulates signal transduction in both striatal output pathways and suggest that PDE10A inhibitors may offer a unique approach to the treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 107 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2010 Aug 34: 1001-6 |
| PMID | 20546816 |
| Title | Effects of olanzapine on brain-derived neurotrophic factor gene promoter activity in SH-SY5Y neuroblastoma cells. |
| Abstract | Atypical antipsychotics have neuroprotective effects, which may be one of the mechanisms for their success in the treatment of schizophrenia. Growing evidence suggest that brain-derived neurotrophic factor (BDNF) is abnormally regulated in patients with schizophrenia, and its expression can be up-regulated by atypical antipsychotics. Atypical antipsychotic drugs may positively regulate transcription of the BDNF gene, but the molecular mechanism of atypical antipsychotic drug action on BDNF gene activity has not been investigated. The aim of the present study was to explore the possible involvement of some intracellular signaling pathways in olanzapine action on BDNF promoter activity. We examined the effects of olanzapine on BDNF gene promoter activity in SH-SY5Y cells transfected with a rat BDNF promoter fragment (-108 to +340) linked to the luciferase reporter gene. The changes in glycogen synthase kinase-3beta (GSK-3beta) and CAMP response element (CRE) binding protein (CREB) phosphorylation were measured by Western blot analysis. Olanzapine treatment (10-100 microM) increased basal BDNF gene promoter activity in a dose-dependent manner and increased protein levels at high dose, and inhibitors of protein kinase A (PKA), H-89 (10 microM), phosphatidylinositol 3-kinase (PI3K), wortmannin (0.01 microM), PKC (protein kinase C), GF109203 (10 microM), calcium/calmodulin kinase II (CaMKII), and KN-93 (20 microM) partially attenuated the stimulatory effect of olanzapine on BDNF promoter activity. In line with these results, a Western blot study showed that olanzapine (100 microM) increased phosphorylated levels of GSK-3beta and CREB, which are notable downstream effectors of the PKA, PI3K, PKC, and CaMKII signaling pathways. These results demonstrate that the up-regulation of olanzapine on BDNF gene transcription is linked with enhancement of CREB-mediated transcription via PKA, PI3K, PKC, and CaMKII signaling pathways, and olanzapine may exert neuroprotective effects through these signaling pathways in neuronal cells. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 108 | PLoS ONE 2010 -1 5: e13452 |
| PMID | 20976142 |
| Title | The dopamine metabolite 3-methoxytyramine is a neuromodulator. |
| Abstract | Dopamine (3-hydroxytyramine) is a well-known catecholamine neurotransmitter involved in multiple physiological functions including movement control. Here we report that the major extracellular metabolite of dopamine, 3-methoxytyramine (3-MT), can induce behavioral effects in a dopamine-independent manner and these effects are partially mediated by the trace amine associated receptor 1 (TAAR1). Unbiased in vivo screening of putative trace amine receptor ligands for potential effects on the movement control revealed that 3-MT infused in the brain is able to induce a complex set of abnormal involuntary movements in mice acutely depleted of dopamine. In normal mice, the central administration of 3-MT caused a temporary mild hyperactivity with a concomitant set of abnormal movements. Furthermore, 3-MT induced significant ERK and CREB phosphorylation in the mouse striatum, signaling events generally related to PKA-mediated CAMP accumulation. In mice lacking TAAR1, both behavioral and signaling effects of 3-MT were partially attenuated, consistent with the ability of 3-MT to activate TAAR1 receptors and cause CAMP accumulation as well as ERK and CREB phosphorylation in cellular assays. Thus, 3-MT is not just an inactive metabolite of DA, but a novel neuromodulator that in certain situations may be involved in movement control. Further characterization of the physiological functions mediated by 3-MT may advance understanding of the pathophysiology and pharmacology of brain disorders involving abnormal dopaminergic transmission, such as Parkinson's disease, dyskinesia and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 109 | J. Neurochem. 2010 Dec 115: 1643-54 |
| PMID | 20969573 |
| Title | Amphetamine modulation of long-term potentiation in the prefrontal cortex: dose dependency, monoaminergic contributions, and paradoxical rescue in hyperdopaminergic mutant. |
| Abstract | Amphetamine can improve cognition in healthy subjects and patients with schizophrenia, attention-deficit hyperactivity disorder, and other neuropsychiatric diseases; higher doses, however, can impair cognitive function, especially those mediated by the prefrontal cortex. We investigated how amphetamine affects prefrontal cortex long-term potentiation (LTP), a cellular correlate of learning and memory, in normal and hyperdopaminergic mice lacking the dopamine transporter. Acute amphetamine treatment in wild-type mice produced a biphasic dose-response modulation of LTP, with a low dose enhancing LTP and a high dose impairing it. Amphetamine-induced LTP enhancement was prevented by pharmacological blockade of D(1) - (but not D(2)-) class dopamine receptors, by blockade of ?-adrenergic receptors, or by inhibition of CAMP-PKA signaling. In contrast, amphetamine-induced LTP impairment was prevented by inhibition of post-synaptic protein phosphatase-1, a downstream target of PKA signaling, or by blockade of either D(1) - or D(2)-class dopamine, but not noradrenergic, receptors. Thus, amphetamine biphasically modulates LTP via CAMP-PKA signaling orchestrated mainly through dopamine receptors. Unexpectedly, amphetamine restored the loss of LTP in dopamine transporter-knockout mice primarily by activation of the noradrenergic system. Our results mirror the biphasic effectiveness of amphetamine in humans and provide new mechanistic insights into its effects on cognition under normal and hyperdopaminergic conditions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 110 | J. Neurosci. 2010 Jul 30: 9027-37 |
| PMID | 20610737 |
| Title | Interplay of palmitoylation and phosphorylation in the trafficking and localization of phosphodiesterase 10A: implications for the treatment of schizophrenia. |
| Abstract | Phosphodiesterase 10A (PDE10A) is a striatum-enriched, dual-specific cyclic nucleotide phosphodiesterase that has gained considerable attention as a potential therapeutic target for psychiatric disorders such as schizophrenia. As such, a PDE10A-selective inhibitor compound, MP-10, has recently entered clinical testing. Since little is known about the cellular regulation of PDE10A, we sought to elucidate the mechanisms that govern its subcellular localization in striatal medium spiny neurons. Previous reports suggest that PDE10A is primarily membrane bound and is transported throughout medium spiny neuron axons and dendrites. Moreover, it has been shown in PC12 cells that the localization of the major splice form, PDE10A2, may be regulated by protein kinase A phosphorylation at threonine 16 (Thr-16). Using an antibody that specifically recognizes phosphorylated Thr-16 (pThr-16) of PDE10A2, we provide evidence that phosphorylation at Thr-16 is critical for the regulation of PDE10A subcellular localization in vivo. Furthermore, we demonstrate in primary mouse striatal neuron cultures that PDE10A membrane association and transport throughout dendritic processes requires palmitoylation of cysteine 11 (Cys-11) of PDE10A2, likely by the palmitoyl acyltransferases DHHC-7 and -19. Finally, we show that Thr-16 phosphorylation regulates PDE10A trafficking and localization by preventing palmitoylation of Cys-11 rather than by interfering with palmitate-lipid interactions. These data support a model whereby PDE10A trafficking and localization can be regulated in response to local fluctuations in CAMP levels. Given this, we propose that excessive striatal dopamine release, as occurs in schizophrenia, might exert differential effects on the regulation of PDE10A localization in the two striatal output pathways. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 111 | Mol. Pharmacol. 2010 Sep 78: 503-10 |
| PMID | 20571078 |
| Title | Regulation of mouse brain-selective sulfotransferase sult4a1 by cAMP response element-binding protein and activating transcription factor-2. |
| Abstract | Sulfotransferase 4A1 (SULT4A1) is a novel cytosolic sulfotransferase that is primarily expressed in the brain. To date, no significant enzyme activity or biological function for the protein has been identified, although it is highly conserved between species. Mutations in the SULT4A1 gene have been linked to schizophrenia susceptibility, and recently, its stability was shown to be regulated by Pin1, a peptidyl-prolyl cis-trans isomerase implicated in several neurodegenerative diseases. In this study, we investigated the transcriptional regulation of mouse Sult4a1. Using a series of promoter deletion constructs, we identified three CAMP-responsive elements (CREs) that were required for maximal promoter activity. The CREs are located within 100 base pairs of the major transcription start site and are also present in the same region of the human SULT4A1 promoter. Electrophoretic mobility shift assays (EMSAs) identified two specific complexes that formed on each of the CREs. One complex contained CAMP response element-binding protein (CREB), and the other contained activating transcription factor-2 (ATF-2) and c-Jun. Overexpression of CREB or ATF-2 increased not only reporter promoter activity but also endogenous Sult4a1 mRNA levels in Neuro2a cells. Moreover, [d-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin (DAMGO) treatment increased both reporter promoter activity and Sult4a1 levels in mu-opioid receptor expressing Neuro2a/mu-opioid receptor cells, and EMSAs showed this to be due to increased binding of CREB and ATF-2 to the Sult4a1 promoter. We also show that DAMGO treatment increases Sult4a1 mRNA and protein levels in primary mouse neurons. These results suggest that Sult4a1 is a target gene for the mu-opioid receptor signaling pathway and other pathways involving activation of CREB and ATF-2. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 112 | Cent Nerv Syst Agents Med Chem 2010 Jun 10: 148-57 |
| PMID | 20518729 |
| Title | New insight into the therapeutic role of 5-HT1A receptors in central nervous system disorders. |
| Abstract | The serotonergic system plays a crucial role in regulating psychoemotional, cognitive and motor functions in the central nervous system (CNS). Among 5-HT receptor subtypes, 5-HT(1A) receptors have long been implicated in the pathogenesis and treatment of anxiety and depressive disorders. 5-HT(1A) receptors function as both presynaptic (autoreceptor) and postsynaptic receptors in specific brain regions such as the limbic areas, septum and raphe nuclei. 5-HT(1A) receptors negatively regulate CAMP-dependent signal transduction and inhibit neuronal activity by opening G-protein-gated inwardly rectifying potassium channels. The therapeutic action of 5-HT(1A) agonists and their mechanism in alleviating anxiety and depressive disorders have been well documented. In addition, recent studies have revealed new insights into the therapeutic role of 5-HT(1A) receptors in treating various CNS disorders, including not only depressive disorders (e.g., delayed onset of action and refractory symptoms), but also schizophrenia (e.g., cognitive impairment and antipsychotic-induced extrapyramidal side effects) and Parkinson's disease (e.g., extrapyramidal motor symptoms and L-DOPA-induced dyskinesia). These lines of evidences encourage us to design new generation 5-HT(1A) ligands such as 5-HT(1A) agonists with greater potency, higher selectivity and improved pharmacokinetic properties, and 5-HT(1A) ligands which combine multiple pharmacological actions (e.g., inhibition of serotonin transporter, dopamine D(2) receptors and other 5-HT receptor subtypes). Such new 5-HT(1A) ligands may overcome clinical efficacy limitations and/or improve adverse reactions in current CNS therapies. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 113 | J. Neurosci. 2010 Feb 30: 2396-405 |
| PMID | 20147565 |
| Title | A subpopulation of neuronal M4 muscarinic acetylcholine receptors plays a critical role in modulating dopamine-dependent behaviors. |
| Abstract | Acetylcholine (ACh) regulates many key functions of the CNS by activating cell surface receptors referred to as muscarinic ACh receptors (M(1)-M(5) mAChRs). Like other mAChR subtypes, the M(4) mAChR is widely expressed in different regions of the forebrain. Interestingly, M(4) mAChRs are coexpressed with D(1) dopamine receptors in a specific subset of striatal projection neurons. To investigate the physiological relevance of this M(4) mAChR subpopulation in modulating dopamine-dependent behaviors, we used Cre/loxP technology to generate mutant mice that lack M(4) mAChRs only in D(1) dopamine receptor-expressing cells. The newly generated mutant mice displayed several striking behavioral phenotypes, including enhanced hyperlocomotor activity and increased behavioral sensitization following treatment with psychostimulants. These behavioral changes were accompanied by a lack of muscarinic inhibition of D(1) dopamine receptor-mediated CAMP stimulation in the striatum and an increase in dopamine efflux in the nucleus accumbens. These novel findings demonstrate that a distinct subpopulation of neuronal M(4) mAChRs plays a critical role in modulating several important dopamine-dependent behaviors. Since enhanced central dopaminergic neurotransmission is a hallmark of several severe disorders of the CNS, including schizophrenia and drug addiction, our findings have substantial clinical relevance. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 114 | Neuroscience 2010 May 167: 287-97 |
| PMID | 20122999 |
| Title | Alpha-2 noradrenergic receptor activation inhibits the hyperpolarization-activated cation current (Ih) in neurons of the ventral tegmental area. |
| Abstract | The ventral tegmental area (VTA) is the source of dopaminergic projections innervating cortical structures and ventral forebrain. Dysfunction of this mesocorticolimbic system is critically involved in psychiatric disorders such as addiction and schizophrenia. Changes in VTA dopamine (DA) neuronal activity can alter neurotransmitter release at target regions which modify information processing in the reward circuit. Here we studied the effect of alpha-2 noradrenergic receptor activation on the hyperpolarization-activated cation current (I(h)) in DA neurons of the rat VTA. Brain slice preparations using whole-cell current and voltage-clamp techniques were employed. Clonidine and UK14304 (alpha-2 receptor selective agonists) were found to decrease I(h) amplitude and to slow its rate of activation indicating a negative shift in the current's voltage dependence. Two non-subtype-selective alpha-2 receptor antagonists, yohimbine and RS79948, prevented the effects of alpha-2 receptor activation. RX821002, a noradrenergic antagonist specific for alpha-2A and alpha-2D did not prevent I(h) inhibition. This result suggests that clonidine might be acting via an alpha-2C subtype since this receptor is the most abundant variant in the VTA. Analysis of a second messenger system associated with the alpha-2 receptor revealed that I(h) inhibition is independent of cyclic AMP (CAMP) and resulted from the activation of protein kinase C. It is suggested that the alpha-2 mediated hyperpolarizing shift in I(h) voltage dependence can facilitate the transition from pacemaker firing to afferent-driven burst activity. This transition may play a key role on the changes in synaptic plasticity that occurs in the mesocorticolimbic system under pathological conditions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 115 | Psychopharmacology (Berl.) 2010 Feb 208: 487-98 |
| PMID | 20013111 |
| Title | A new model of the disrupted latent inhibition in C57BL/6J mice after bupropion treatment. |
| Abstract | schizophrenia is characterized by disturbances in attention and information processing that can be measured by latent inhibition (LI). Research has implicated significant aberrations in dopaminergic (DA) neurotransmission in this disorder. The objectives of this study were as follows: to probe whether bupropion disrupts LI; to compare its efficacy to the effects of GBR12783 (specific DA uptake inhibitor) and to amphetamine (DA releaser); to test if antipsychotics would reverse LI deficits induced by bupropion, GBR12783, and amphetamine; and to probe if rolipram (phosphodiesterase-4 inhibitor), which increases cyclic AMP (CAMP) similarly to antipsychotics, effectively corrects drug-induced LI deficits. Based on its efficacy in drug addiction, we also asked if bupropion could block the effect of amphetamine. LI was measured in a conditioned emotional response procedure by comparing suppression of drinking in response to a noise in C57BL/6J mice. Mice previously received 0 (nonpreexposed) or 40 noise exposures (preexposed) followed by two or four noise-foot shock pairings. Bupropion abolished LI in mice, which was corrected by rolipram, but not by haloperidol and clozapine. GBR12783 and amphetamine, but not antidepressants, also disrupted LI, and this was reversed by antipsychotics and rolipram. Both bupropion and amphetamine disrupted LI via conditioning session. Paradoxically, bupropion and GBR12783 also blocked the amphetamine-induced LI deficit. Efficacy of rolipram but not antipsychotics to reverse the effects of bupropion suggests novel CAMP-dependent and D(2) receptor-independent mechanisms of the bupropion-induced LI deficit. Further detailed biochemical analysis of bupropion-induced LI deficit might be a fruitful approach in developing new antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 116 | Proc. Natl. Acad. Sci. U.S.A. 2011 Dec 108: E1349-58 |
| PMID | 22049344 |
| Title | Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice. |
| Abstract | Carefully designed animal models of genetic risk factors are likely to aid our understanding of the pathogenesis of schizophrenia. Here, we study a mouse strain with a truncating lesion in the endogenous Disc1 ortholog designed to model the effects of a schizophrenia-predisposing mutation and offer a detailed account of the consequences that this mutation has on the development and function of a hippoCAMPal circuit. We uncover widespread and cumulative cytoarchitectural alterations in the dentate gyrus during neonatal and adult neurogenesis, which include errors in axonal targeting and are accompanied by changes in short-term plasticity at the mossy fiber/CA3 circuit. We also provide evidence that CAMP levels are elevated as a result of the Disc1 mutation, leading to altered axonal targeting and dendritic growth. The identified structural alterations are, for the most part, not consistent with the growth-promoting and premature maturation effects inferred from previous RNAi-based Disc1 knockdown. Our results provide support to the notion that modest disturbances of neuronal connectivity and accompanying deficits in short-term synaptic dynamics is a general feature of schizophrenia-predisposing mutations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 117 | Front Mol Neurosci 2011 -1 4: 38 |
| PMID | 22065948 |
| Title | Beyond cAMP: The Regulation of Akt and GSK3 by Dopamine Receptors. |
| Abstract | Brain dopamine receptors have been preferred targets for numerous pharmacological compounds developed for the treatment of various neuropsychiatric disorders. Recent discovery that D2 dopamine receptors, in addition to CAMP pathways, can engage also in Akt/GSK3 signaling cascade provided a new framework to understand intracellular signaling mechanisms involved in dopamine-related behaviors and pathologies. Here we review a recent progress in understanding the role of Akt, GSK3, and related signaling molecules in dopamine receptor signaling and functions. Particularly, we focus on the molecular mechanisms involved, interacting partners, role of these signaling events in the action of antipsychotics, psychostimulants, and antidepressants as well as involvement in pathophysiology of schizophrenia, bipolar disorder, and Parkinson's disease. Further understanding of the role of Akt/GSK3 signaling in dopamine receptor functions could provide novel targets for pharmacological interventions in dopamine-related disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 118 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2011 Dec 35: 1901-7 |
| PMID | 21821092 |
| Title | Profiles of DARPP-32 in the insular cortex with schizophrenia: a postmortem brain study. |
| Abstract | In patients with schizophrenia, various physical disorders are sometimes discovered only when they have reached a later and more severe stage. This phenomenon is believed to be caused, at least in part, by an increase in pain threshold. The gamma-aminobutyric acid (GABA)-ergic and glutamatergic systems in the rostral agranular insular cortex (RAIC) are thought to be involved in the regulation of pain threshold. However, no postmortem studies of the cerebral cortex have previously been published. Dopamine and CAMP-regulated phosphoprotein 32 kD (DARPP-32), which is involved in the GABAergic and glutamatergic systems, is considered to be crucial for elucidating the pathogenesis of schizophrenia. Using specific antibodies, we conducted immunohistochemical examinations of the RAIC in 10 subjects from a healthy control group, and 11 subjects from a schizophrenia group. The sex, age, and postmortem interval (PMI) of the schizophrenia group were matched to those of the healthy control group. We revealed that the density of DARPP-32-immunoreactive (IR) neurons in the II and III layers of the RAIC was significantly decreased (p<0.05) in the schizophrenia group compared with the healthy control group. Our findings could partially explain the molecular basis of the pain threshold abnormalities found in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 119 | J. Neurosci. 2011 Jun 31: 9043-54 |
| PMID | 21677187 |
| Title | PKA phosphorylation of NDE1 is DISC1/PDE4 dependent and modulates its interaction with LIS1 and NDEL1. |
| Abstract | Nuclear distribution factor E-homolog 1 (NDE1), Lissencephaly 1 (LIS1), and NDE-like 1 (NDEL1) together participate in essential neurodevelopmental processes, including neuronal precursor proliferation and differentiation, neuronal migration, and neurite outgrowth. NDE1/LIS1/NDEL1 interacts with Disrupted in schizophrenia 1 (DISC1) and the CAMP-hydrolyzing enzyme phosphodiesterase 4 (PDE4). DISC1, PDE4, NDE1, and NDEL1 have each been implicated as genetic risk factors for major mental illness. Here, we demonstrate that DISC1 and PDE4 modulate NDE1 phosphorylation by CAMP-dependent protein kinase A (PKA) and identify a novel PKA substrate site on NDE1 at threonine-131 (T131). Homology modeling predicts that phosphorylation at T131 modulates NDE1-LIS1 and NDE1-NDEL1 interactions, which we confirm experimentally. DISC1-PDE4 interaction thus modulates organization of the NDE1/NDEL1/LIS1 complex. T131-phosphorylated NDE1 is present at the postsynaptic density, in proximal axons, within the nucleus, and at the centrosome where it becomes substantially enriched during mitosis. Mutation of the NDE1 T131 site to mimic PKA phosphorylation inhibits neurite outgrowth. Thus PKA-dependent phosphorylation of the NDE1/LIS1/NDEL1 complex is DISC1-PDE4 modulated and likely to regulate its neural functions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 120 | Curr. Pharm. Des. 2011 -1 17: 137-50 |
| PMID | 21355834 |
| Title | PDE10A inhibitors: novel therapeutic drugs for schizophrenia. |
| Abstract | Disturbances of the basal ganglia processes is heavily involved in schizophrenia. Phosphodiesterase 10A (PDE10A) is a basal ganglia specific hydrolase, which plays an essential role in regulating CAMP/PKA and cGMP/PKG signalling cascades by controlling the magnitude, duration and cellular location of CAMP/cGMP elevation. Biochemical and behavioral data indicate that PDE10A inhibition activates CAMP/PKA signalling in the basal ganglia, leading to the potentiation of dopamine D? receptor signalling, and concomitant inhibition of dopamine D? receptor signalling. Preclinical evidence in a range of animal models suggests that a PDE10A inhibitor could provide efficacy on positive, cognitive and negative symptoms of schizophrenia and PDE10A inhibitors are currently being evaluated in clinical trials for the treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 121 | Transl Psychiatry 2011 -1 1: e9 |
| PMID | 22832404 |
| Title | Convergent functional genomics of anxiety disorders: translational identification of genes, biomarkers, pathways and mechanisms. |
| Abstract | Anxiety disorders are prevalent and disabling yet understudied from a genetic standpoint, compared with other major psychiatric disorders such as bipolar disorder and schizophrenia. The fact that they are more common, diverse and perceived as embedded in normal life may explain this relative oversight. In addition, as for other psychiatric disorders, there are technical challenges related to the identification and validation of candidate genes and peripheral biomarkers. Human studies, particularly genetic ones, are susceptible to the issue of being underpowered, because of genetic heterogeneity, the effect of variable environmental exposure on gene expression, and difficulty of accrual of large, well phenotyped cohorts. Animal model gene expression studies, in a genetically homogeneous and experimentally tractable setting, can avoid artifacts and provide sensitivity of detection. Subsequent translational integration of the animal model datasets with human genetic and gene expression datasets can ensure cross-validatory power and specificity for illness. We have used a pharmacogenomic mouse model (involving treatments with an anxiogenic drug--yohimbine, and an anti-anxiety drug--diazepam) as a discovery engine for identification of anxiety candidate genes as well as potential blood biomarkers. Gene expression changes in key brain regions for anxiety (prefrontal cortex, amygdala and hippoCAMPus) and blood were analyzed using a convergent functional genomics (CFG) approach, which integrates our new data with published human and animal model data, as a translational strategy of cross-matching and prioritizing findings. Our work identifies top candidate genes (such as FOS, GABBR1, NR4A2, DRD1, ADORA2A, QKI, RGS2, PTGDS, HSPA1B, DYNLL2, CCKBR and DBP), brain-blood biomarkers (such as FOS, QKI and HSPA1B), pathways (such as CAMP signaling) and mechanisms for anxiety disorders--notably signal transduction and reactivity to environment, with a prominent role for the hippoCAMPus. Overall, this work complements our previous similar work (on bipolar mood disorders and schizophrenia) conducted over the last decade. It concludes our programmatic first pass mapping of the genomic landscape of the triad of major psychiatric disorder domains using CFG, and permitted us to uncover the significant genetic overlap between anxiety and these other major psychiatric disorders, notably the under-appreciated overlap with schizophrenia. PDE10A, TAC1 and other genes uncovered by our work provide a molecular basis for the frequently observed clinical co-morbidity and interdependence between anxiety and other major psychiatric disorders, and suggest schizo-anxiety as a possible new nosological domain. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 122 | Int. J. Neuropsychopharmacol. 2011 Aug 14: 941-53 |
| PMID | 20942999 |
| Title | Abnormalities in ?/?-CaMKII and related mechanisms suggest synaptic dysfunction in hippocampus of LPA1 receptor knockout mice. |
| Abstract | Lysophosphatidic acid (LPA) is a natural lysophospholipid that regulates neuronal maturation. In mice, the deletion of the LPA1 receptor causes some phenotypic defects partly overlapping with those found in schizophrenia. In this study, we identified molecular abnormalities in hippoCAMPal synaptic mechanisms involved in glutamatergic neurotransmission, which allow further characterization of synaptic aberrations in LPA1 knockout (KO) mice. At the synaptic level, we found dysregulation of Ca2+/calmodulin (CaM)-dependent kinase II (CaMKII) activity and phosphorylation, with markedly higher Ca2+-dependent kinase activity, probably related to increased expression levels of the ? isoform of CaMKII. Conversely, although the synaptic Ca2+-independent activity of the enzyme was unchanged, autophosphorylation levels of both ? and ? isoforms were significantly increased in LPA1 KO mice. Moreover, in LPA1 KO mice the ?/? isoform ratio of CaMKII, which plays a key role in neuronal maturation during development, was markedly decreased, as found previously in schizophrenia patients. At post-synaptic level, LPA1 KO mice showed changes in expression, phosphorylation and interactions of NMDA and AMPA receptor subunits that are consistent with basal strengthening of glutamatergic synapses. However, we measured a reduction of nuclear CAMP responsive element-binding protein phosphorylation, suggesting that activation of the NMDA receptor does not occur at the intracellular signalling level. At the presynaptic level, in line with previous evidence from schizophrenia patients and animal models of pathology, LPA1 KO mice showed accumulation of SNARE protein complexes. This study shows that CaMKII and related synaptic mechanisms at glutamatergic synapses are strongly dysregulated in LPA1 KO mice. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 123 | PLoS ONE 2011 -1 6: e18113 |
| PMID | 21448290 |
| Title | Correlated alterations in serotonergic and dopaminergic modulations at the hippocampal mossy fiber synapse in mice lacking dysbindin. |
| Abstract | Dysbindin-1 (dystrobrevin-binding protein 1, DTNBP1) is one of the promising schizophrenia susceptibility genes. Dysbindin protein is abundantly expressed in synaptic regions of the hippoCAMPus, including the terminal field of the mossy fibers, and this hippoCAMPal expression of dysbindin is strongly reduced in patients with schizophrenia. In the present study, we examined the functional role of dysbindin in hippoCAMPal mossy fiber-CA3 synaptic transmission and its modulation using the sandy mouse, a spontaneous mutant with deletion in the dysbindin gene. Electrophysiological recordings were made in hippoCAMPal slices prepared from adult male sandy mice and their wild-type littermates. Basic properties of the mossy fiber synaptic transmission in the mutant mice were generally normal except for slightly reduced frequency facilitation. Serotonin and dopamine, two major neuromodulators implicated in the pathophysiology of schizophrenia, can potentiate mossy fiber synaptic transmission probably via an increase in CAMP levels. Synaptic potentiation induced by serotonin and dopamine was very variable in magnitude in the mutant mice, with some mice showing prominent enhancement as compared with the wild-type mice. In addition, the magnitude of potentiation induced by these monoamines significantly correlated with each other in the mutant mice, indicating that a subpopulation of sandy mice has marked hypersensitivity to both serotonin and dopamine. While direct activation of the CAMP cascade by forskolin induced robust synaptic potentiation in both wild-type and mutant mice, this forskolin-induced potentaition correlated in magnitude with the serotonin-induced potentiation only in the mutant mice, suggesting a possible change in coupling of receptor activation to downstream signaling. These results suggest that the dysbindin deficiency could be an essential genetic factor that causes synaptic hypersensitivity to dopamine and serotonin. The altered monoaminergic modulation at the mossy fiber synapse could be a candidate pathophysiological basis for impairment of hippoCAMPus-dependent brain functions in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 124 | Med Mol Morphol 2011 Dec 44: 190-9 |
| PMID | 22179181 |
| Title | Detailed DARPP-32 expression profiles in postmortem brains from patients with schizophrenia: an immunohistochemical study. |
| Abstract | The prevalence of dopamine and CAMP-regulated phosphoprotein 32kD (DARPP-32) is associated with the pathogenesis of schizophrenia. To date, the findings on DARPP-32 cellular expression and distribution in postmortem brains from patients with schizophrenia have been inconsistent. To clarify the detailed cellular expression of DARPP-32 in patients with schizophrenia, we immunohistochemically stained sections from postmortem brains using specific antibodies. We measured the density of immunopositive cells in various brain regions including the prefrontal cortex and compared the data from nine schizophrenia subjects with those of nine age- and sex-matched control subjects. The density of DARPP-32-immunoreactive (IR) neurons was significantly lower in layers II-V of the dorsolateral prefrontal cortex (DLPFC) from subjects with schizophrenia. In contrast, there were no marked differences in DARPP-32 expression in other brain regions. In addition, the density of threonine (Thr34)-phosphorylated DARPP-32-IR neurons was significantly higher in layer V of DLPFC from subjects with schizophrenia. These results suggest that the decrease in DARPP-32 in schizophrenia was more marked in neurons of DLPFC than in other cells or other brain regions, and that this decrease might be partly compensated for by an increase in expression of Thr34-phosphorylated DARPP-32 in DLPFC. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 125 | Int J Mol Sci 2011 -1 12: 5999-6023 |
| PMID | 22016641 |
| Title | Investigation on quantitative structure activity relationships and pharmacophore modeling of a series of mGluR2 antagonists. |
| Abstract | MGluR2 is G protein-coupled receptor that is targeted for diseases like anxiety, depression, Parkinson's disease and schizophrenia. Herein, we report the three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of a series of 1,3-dihydrobenzo[ b][1,4]diazepin-2-one derivatives as mGluR2 antagonists. Two series of models using two different activities of the antagonists against rat mGluR2, which has been shown to be very similar to the human mGluR2, (activity I: inhibition of [(3)H]-LY354740; activity II: mGluR2 (1S,3R)-ACPD inhibition of forskolin stimulated CAMP.) were derived from datasets composed of 137 and 69 molecules respectively. For activity I study, the best predictive model obtained from CoMFA analysis yielded a Q(2) of 0.513, R(2) (ncv) of 0.868, R(2) (pred) = 0.876, while the CoMSIA model yielded a Q(2) of 0.450, R(2) (ncv) = 0.899, R(2) (pred) = 0.735. For activity II study, CoMFA model yielded statistics of Q(2) = 0.5, R(2) (ncv) = 0.715, R(2) (pred) = 0.723. These results prove the high predictability of the models. Furthermore, a combined analysis between the CoMFA, CoMSIA contour maps shows that: (1) Bulky substituents in R(7), R(3) and position A benefit activity I of the antagonists, but decrease it when projected in R(8) and position B; (2) Hydrophilic groups at position A and B increase both antagonistic activity I and II; (3) Electrostatic field plays an essential rule in the variance of activity II. In search for more potent mGluR2 antagonists, two pharmacophore models were developed separately for the two activities. The first model reveals six pharmacophoric features, namely an aromatic center, two hydrophobic centers, an H-donor atom, an H-acceptor atom and an H-donor site. The second model shares all features of the first one and has an additional acceptor site, a positive N and an aromatic center. These models can be used as guidance for the development of new mGluR2 antagonists of high activity and selectivity. This work is the first report on 3D-QSAR modeling of these mGluR2 antagonists. All the conclusions may lead to a better understanding of the mechanism of antagonism and be helpful in the design of new potent mGluR2 antagonists. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 126 | Front Behav Neurosci 2011 -1 5: 56 |
| PMID | 21927600 |
| Title | DARPP-32, Jack of All Trades? Master of Which? |
| Abstract | DARPP-32 (PPP1R1B) was discovered as a substrate of CAMP-dependent protein kinase (PKA) enriched in dopamine-innervated brain areas. It is one of three related, PKA-regulated inhibitors of protein phosphatase-1 (PP1). These inhibitors seem to have appeared in early vertebrate ancestors, possibly Gnathostomes. DARPP-32 has additional important biochemical properties including inhibition of PKA when phosphorylated by Cdk5 and regulation by casein kinases 1 and 2. It is highly enriched in specific neuronal populations, especially striatal medium-size spiny neurons. As PP1 inhibitor DARPP-32 amplifies and/or mediates many actions of PKA at the plasma membrane and in the cytoplasm, with a broad spectrum of potential targets and functions. DARPP-32 also undergoes a continuous and tightly regulated cytonuclear shuttling. This trafficking is controlled by phosphorylation of Ser-97, which is necessary for nuclear export. When phosphorylated on Thr-34 and dephosphorylated on Ser-97, DARPP-32 can inhibit PP1 in the nucleus and modulate signaling pathways involved in the regulation of chromatin response. Recent work with multiple transgenic and knockout mutant mice has allowed the dissection of DARPP-32 function in striato-nigral and striato-pallidal neurons. It is implicated in the action of therapeutic and abused psychoactive drugs, in prefrontal cortex function, and in sexual behavior. However, the contribution of DARPP-32 in human behavior remains poorly understood. Post-mortem studies in humans suggest possible alterations of DARPP-32 levels in schizophrenia and bipolar disorder. Genetic studies have revealed a polymorphism with possible association with psychological and psychopathological traits. In addition, a short isoform of DARPP-32, t-DARPP, plays a role in cancer, indicating additional signaling properties. Thus, DARPP-32 is a non-essential but tightly regulated signaling hub molecule which may improve the general performance of the neuronal circuits in which it is expressed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 127 | Neuropharmacology 2011 Dec 61: 1275-81 |
| PMID | 21816164 |
| Title | The PDE10A inhibitor, papaverine, differentially activates ERK in male and female rat striatal slices. |
| Abstract | The phosphodiesterase 10A (PDE10A) is highly expressed within dopaminoreceptive medium spiny neurons (MSNs) of the striatum, which are implicated in various neurodegenerative diseases and psychiatric disorders, such as Huntington's disease and schizophrenia. With its dual action on CAMP and cGMP, PDE10A has been proposed to affect several signaling cascades in the corticostriatothalamic circuits. In particular, papaverine, a selective PDE10A inhibitor has been shown to activate/phosphorylate ERK in striatum. We used acute rat striatal slices to further characterize the effects of papaverine on ERK activation/phosphorylation in D1- and D2-responsive striatal neurons. Incubation of striatal slices from male rats with papaverine increased the levels of phospho-ERK1/2 (p-ERK), an effect enhanced with a D1 agonist or a D2 antagonist, but decreased with a D1 receptor antagonist or a D2 receptor agonist. Papaverine-induced increase in p-ERK was localized in striatal neurons receiving D1-enriched presynaptic terminals, as well as in postsynaptic D2-enriched neurons in striatal slices. Interestingly, papaverine had almost no stimulatory effects on ERK1/2 phosphorylation in slices prepared from female rats. In striatal slices prepared from ovariectomized female rats, papaverine treatment stimulated ERK1/2 phosphorylation to levels similar to those in slices from male rats. Moreover, estrogen was found to regulate the levels of D2 but not D1 receptors in striatum. These results indicate that circulating levels of female hormones, and in particular estrogen, regulate the effects of PDE10A inhibition on ERK1/2 phosphorylation in medium spiny neurons, an effect possibly linked to estrogen's regulation of D2 receptors. Considering the variety of events modulated by ERK1/2 activity, these findings suggest that sex difference needs to be taken into consideration for the further investigation of the effects of PDE10A inhibitors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 128 | Front Neuroanat 2011 -1 5: 38 |
| PMID | 21808606 |
| Title | Deciphering the Actions of Antiparkinsonian and Antipsychotic Drugs on cAMP/DARPP-32 Signaling. |
| Abstract | The basal ganglia are affected by several neuropsychiatric and neurodegenerative diseases, many of which are treated with drugs acting on the dopamine system. For instance, the loss of dopaminergic input to the striatum, which is the main pathological feature of Parkinson's disease, is counteracted by administering the dopamine precursor, L-DOPA. Furthermore, psychotic disorders, including schizophrenia, are treated with drugs that act as antagonists at the D2-type of dopamine receptor (D2R). The use of L-DOPA and typical antipsychotic drugs, such as haloperidol, is limited by the emergence of motor side-effects, particularly after prolonged use. Striatal medium spiny neurons (MSNs) represent an ideal tool to investigate the molecular changes implicated in these conditions. MSNs receive a large glutamatergic innervation from cortex, thalamus, and limbic structures, and are controlled by dopaminergic projections originating in the midbrain. There are two large populations of striatal MSNs, which differ based on their connectivity to the output nuclei of the basal ganglia and on their ability to express dopamine D1 receptors (D1Rs) or D2Rs. Administration of L-DOPA promotes CAMP signaling and activates the dopamine- and CAMP-regulated phosphoprotein of 32?kDa (DARPP-32) in the D1R-expressing MSNs, which form the striatonigral, or direct pathway. Conversely, haloperidol activates the CAMP/DARPP-32 cascade in D2R-expressing MSNs, which form the striatopallidal, or indirect pathway. This review describes the effects produced on downstream effector proteins by stimulation of CAMP/DARPP-32 signaling in these two groups of MSNs. Particular emphasis is given to the regulation of the GluR1 subunit of the ?-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate glutamate receptor, the extracellular signal-regulated protein kinases 1 and 2, focusing on functional role and potential pathological relevance. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 129 | Am J Psychiatry 2011 Sep 168: 947-56 |
| PMID | 21768610 |
| Title | A randomized trial examining the effectiveness of switching from olanzapine, quetiapine, or risperidone to aripiprazole to reduce metabolic risk: comparison of antipsychotics for metabolic problems (CAMP). |
| Abstract | The authors conducted a multisite randomized controlled trial examining the strategy of switching from olanzapine, quetiapine, or risperidone to aripiprazole to ameliorate metabolic risk factors for cardiovascular disease. Patients with schizophrenia or schizoaffective disorder with a body mass index ? 27 and non-high-density lipoprotein (non-HDL) cholesterol ? 130 mg/dl who were on a stable treatment dosage of olanzapine, quetiapine, or risperidone were randomly assigned to switch to ari-piprazole (N=109) for 24 weeks or stay on their current medication (N=106). All participants were enrolled in a behaviorally oriented diet and exercise program. Clinical raters were blinded to treatment assignment. The primary and key secondary outcomes were change in non-HDL cholesterol and efficacy failure, respectively. The prespecified primary analysis included 89 switchers and 98 stayers who had at least one postbaseline non-HDL cholesterol measurement. The least squares mean estimates of non-HDL cholesterol decreased more for the switch group than for the stay group (-20.2 mg/dl and -10.8 mg/dl, respectively). Switching was associated with larger weight reductions (least squares mean=2.9 kg) and a net reduction of serum triglycerides of 32.7 mg/dl. Twenty-two switchers (20.6%) and 18 stayers (17.0%) experienced protocol-defined efficacy failure. Forty-seven switchers (43.9%) and 26 stayers (24.5%) discontinued the assigned antipsychotic medication before 24 weeks. Switching to aripiprazole led to improvement of non-HDL cholesterol levels and other metabolic parameters. Rates of efficacy failure were similar between groups, but switching to aripiprazole was associated with a higher rate of treatment discontinuation. In the context of close clinical monitoring, switching from an antipsychotic with high metabolic risk to one with lower risk to improve metabolic parameters is an effective strategy. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 130 | Eur. J. Pharmacol. 2011 Sep 666: 43-52 |
| PMID | 21658377 |
| Title | Functional potencies of dopamine agonists and antagonists at human dopamine D? and D? receptors. |
| Abstract | We measured the functional agonist potencies of dopamine agonists including antiparkinson drugs, and functional antagonist potencies of antipsychotics at human dopamine D(2) and D(3) receptors. In vitro pharmacological assessment included inhibition of forskolin-stimulated CAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cells expressing low and high densities of human dopamine D(2L) and D(2S) receptors (hD(2L)-Low, hD(2L)-High, hD(2S)-Low and hD(2S)-High, respectively) and human dopamine D(3) Ser-9 and D(3) Gly-9 receptors (hD(3)-Ser-9 and hD(3)-Gly-9, respectively). Cabergoline, bromocriptine, pergolide, (±)-7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), talipexole, pramipexole, R-(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-olhydrochloride (PD128907) and ropinirole behaved as dopamine D(2) and D(3) receptor full agonists and showed higher potencies in hD(2L)-High and hD(2S)-High compared to hD(2L)-Low and hD(2S)-Low. In hD(3)-Ser-9 and hD(3)-Gly-9 compared to hD(2L)-Low and hD(2S)-Low, dopamine, ropinirole, PD128907, and pramipexole potencies were clearly higher; talipexole and 7-OH-DPAT showed slightly higher potencies; pergolide showed slightly lower potency; and, cabergoline and bromocriptine potencies were lower. Aripiprazole acted as an antagonist in hD(2L)-Low; a low intrinsic activity partial agonist in hD(2S)-Low; a moderate partial agonist in hD(3)-Ser-9 and hD(3)-Gly-9; a robust partial agonist in hD(2L)-High; and a full agonist in hD(2S)-High. Amisulpride, sulpiride and perphenazine behaved as preferential antagonists; and chlorpromazine and asenapine behaved as modest preferential antagonists; whereas fluphenazine, haloperidol, and blonanserin behaved as non-preferential antagonists in hD(2S)-Low and hD(2S)-High compared to hD(3)-Ser-9 and hD(3)-Gly-9. These findings may help to elucidate the basis of therapeutic benefit observed with these drugs, with varying mechanisms of action, in the treatment of Parkinson's disease, depression and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 131 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2011 Jun 35: 1139-43 |
| PMID | 21453742 |
| Title | Altered DARPP-32 expression in the superior temporal gyrus in schizophrenia. |
| Abstract | Many neuroimaging studies have revealed structural abnormalities in the superior temporal gyrus (STG) in schizophrenia (Kasai et al., 2003a, 2003b; Sun et al., 2009). Neurophysiological studies of mismatch negativities (MMN) generated in the STG have suggested impaired function of N-methyl-d-aspartate (NMDA) receptors (Javitt et al., 1996). Although many postmortem studies have been conducted on the pathogenesis of schizophrenia, relatively few reports have studied molecular alterations in the STG (Bowden et al., 2008; Deng and Huang, 2006; Kang et al., 2009; Katsel et al., 2005; Le Corre et al., 2000; Nudmamud and Reynolds, 2001; Sokolov et al., 2000). The STG shows pronounced changes in gene expression when compared to other regions implicated in schizophrenia (Katsel et al., 2005). Dopamine and a CAMP-regulated phosphoprotein of molecular weight 32kDa (DARPP-32) is thought to be closely associated with pathophysiological changes in the dopamine and glutamate systems in schizophrenia because, when activated by phosphorylation, DARPP-32 acts as a critical regulator of D1 dopamine receptor and NMDA receptor activity (Greengard et al., 1999). The molecular pathways involving DARPP-32 appear important in the pathogenesis of schizophrenia. Here, we show dramatic alterations in DARPP-32 expression in the STG of postmortem brains from patients with schizophrenia. To clarify the detailed histological and cellular expression of DARPP-32 in the STG in schizophrenia, we immunohistochemically examined postmortem brains by using specific antibodies. We compared the density of immunoreactive cells of the STG (BA22) from 11 schizophrenia patients with those from 11 age- and sex-matched controls, and found significantly lower densities of DARPP-32-immunoreactive (IR) cells and threonine (Thr) 34-phosphorylated DARPP-32-IR cells in the STG in the schizophrenia group. Thus, the DARPP-32-related pathogenesis in schizophrenia may be more severe in the STG than previously found in the prefrontal cortex. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 132 | Int. J. Dev. Neurosci. 2011 May 29: 215-23 |
| PMID | 21345366 |
| Title | Prefrontal cortical network connections: key site of vulnerability in stress and schizophrenia. |
| Abstract | The symptoms of schizophrenia involve profound dysfunction of the prefrontal cortex (PFC). PFC networks create our "mental sketch pad", and PFC dysfunction contributes to symptoms such as cognitive deficits, thought disorder, delusions and hallucinations. Neuropathological studies of schizophrenia have shown marked loss of dendritic spines in deep layer III, the sublayer where PFC microcircuits reside. The microcircuits consist of recurrent excitatory pyramidal cell networks that interconnect on spines, and excite each other via NMDA receptor signaling. The pyramidal cell persistent firing is sculpted by lateral inhibition from GABAergic basket and chandelier cells, thus creating tuned, persistent firing needed for accurate representational knowledge (i.e., working memory). The strength of pyramidal cell network connections is markedly and flexibly altered by intracellular signaling pathways in dendritic spines, a process called dynamic network connectivity (DNC). DNC proteins such as HCN channels are concentrated on dendritic spines in deep layer III. Under optimal conditions, network inputs to pyramidal cells are strengthened by noradrenergic alpha-2A inhibition of CAMP-HCN channel signaling, and sculpted by dopamine D1-CAMP-HCN channel weakening of inappropriate inputs. However, with stress exposure, high levels of CAMP-HCN channel signaling produces a collapse in network firing. With chronic stress exposure, spines reduce in size and are lost, and this process involves increased PKC signaling. Importantly, molecules that normally strengthen PFC networks connections and/or reverse the stress response, are often genetically altered in schizophrenia. As exposure to stress is a key factor in the precipitation of schizophrenic symptoms, these dysregulated signaling pathways in deep layer III may interact with already vulnerable circuitry to cause spine loss and the descent into illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 133 | Biochem. J. 2011 May 435: 755-69 |
| PMID | 21323643 |
| Title | Phosphorylation of cAMP-specific PDE4A5 (phosphodiesterase-4A5) by MK2 (MAPKAPK2) attenuates its activation through protein kinase A phosphorylation. |
| Abstract | CAMP-specific PDE (phosphodiesterase) 4 isoforms underpin compartmentalized CAMP signalling in mammalian cells through targeting to specific signalling complexes. Their importance is apparent as PDE4 selective inhibitors exert profound anti-inflammatory effects and act as cognitive enhancers. The p38 MAPK (mitogen-activated protein kinase) signalling cascade is a key signal transduction pathway involved in the control of cellular immune, inflammatory and stress responses. In the present study, we show that PDE4A5 is phosphorylated at Ser147, within the regulatory UCR1 (ultraconserved region 1) domain conserved among PDE4 long isoforms, by MK2 (MAPK-activated protein kinase 2, also called MAPKAPK2). Phosphorylation by MK2, although not altering PDE4A5 activity, markedly attenuates PDE4A5 activation through phosphorylation by protein kinase A. This modification confers the amplification of intracellular CAMP accumulation in response to adenylate cyclase activation by attenuating a major desensitization system to CAMP. Such reprogramming of CAMP accumulation is recapitulated in wild-type primary macrophages, but not MK2/3-null macrophages. Phosphorylation by MK2 also triggers a conformational change in PDE4A5 that attenuates PDE4A5 interaction with proteins whose binding involves UCR2, such as DISC1 (disrupted in schizophrenia 1) and AIP (aryl hydrocarbon receptor-interacting protein), but not the UCR2-independent interacting scaffold protein ?-arrestin. Long PDE4 isoforms thus provide a novel node for cross-talk between the CAMP and p38 MAPK signalling systems at the level of MK2. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 134 | Pharmacol. Rev. 2011 Mar 63: 182-217 |
| PMID | 21303898 |
| Title | The physiology, signaling, and pharmacology of dopamine receptors. |
| Abstract | G protein-coupled dopamine receptors (D1, D2, D3, D4, and D5) mediate all of the physiological functions of the catecholaminergic neurotransmitter dopamine, ranging from voluntary movement and reward to hormonal regulation and hypertension. Pharmacological agents targeting dopaminergic neurotransmission have been clinically used in the management of several neurological and psychiatric disorders, including Parkinson's disease, schizophrenia, bipolar disorder, Huntington's disease, attention deficit hyperactivity disorder (ADHD(1)), and Tourette's syndrome. Numerous advances have occurred in understanding the general structural, biochemical, and functional properties of dopamine receptors that have led to the development of multiple pharmacologically active compounds that directly target dopamine receptors, such as antiparkinson drugs and antipsychotics. Recent progress in understanding the complex biology of dopamine receptor-related signal transduction mechanisms has revealed that, in addition to their primary action on CAMP-mediated signaling, dopamine receptors can act through diverse signaling mechanisms that involve alternative G protein coupling or through G protein-independent mechanisms via interactions with ion channels or proteins that are characteristically implicated in receptor desensitization, such as ?-arrestins. One of the future directions in managing dopamine-related pathologic conditions may involve a transition from the approaches that directly affect receptor function to a precise targeting of postreceptor intracellular signaling modalities either directly or through ligand-biased signaling pharmacology. In this comprehensive review, we discuss dopamine receptor classification, their basic structural and genetic organization, their distribution and functions in the brain and the periphery, and their regulation and signal transduction mechanisms. In addition, we discuss the abnormalities of dopamine receptor expression, function, and signaling that are documented in human disorders and the current pharmacology and emerging trends in the development of novel therapeutic agents that act at dopamine receptors and/or on related signaling events. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 135 | Transl Psychiatry 2011 -1 1: e22 |
| PMID | 22832524 |
| Title | Association of VSNL1 with schizophrenia, frontal cortical function, and biological significance for its gene product as a modulator of cAMP levels and neuronal morphology. |
| Abstract | We report an association of single-nucleotide polymorphisms (SNPs) for the VSNL1 gene (visinin-like 1) with schizophrenia and frontal cortical function in a sample of patients with Diagnostic and Statistical Manual of Mental Disorder-IV (DSM-IV) diagnoses of schizophrenia, compared with healthy controls. Moreover, VSNL1 SNPs were associated with performance in the Wisconsin Card Sorting Test, a measure for the assessment of frontal cortical function. The VSNL1 gene product, Visinin-like-protein-1 (VILIP-1), is a member of the neuronal EF-hand Ca(2+)-sensor protein family. Previously, VILIP-1 mRNA and protein expression were shown to be altered in animal models and in schizophrenia patients. VILIP-1 influences cytosolic cyclic adenosine mono phosphate (CAMP) levels, cell migration, exocytotic processes and differentiation in the periphery. This raises the question, whether, similar to other potential schizophrenia susceptibility genes such as Disc1, PDE4B and Akt, VSNL1 may affect CAMP signaling and neurite outgrowth in neurons. In dissociated rat hippoCAMPal neurons, VILIP-1 small interfering RNA knockdown decreased CAMP levels and reduced dendrite branching, compared with control-transfected cells. In contrast, VILIP-1 overexpression had the opposite effect. Similar results have been obtained in the human dopaminergic neuronal cell line SH-SY5Y, where the effect on neurite branching and length was attenuated by the adenylyl cyclase inhibitor 2',5'-dideoxyadenosine and the protein kinase A inhibitor KT5720. These results show that the association of VSNL1 SNPs with the disease and cognitive impairments, together with previously observed pathological changes in VILIP-1 protein expression, possibly occurring during brain development, may contribute to the morphological and functional deficits observed in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 136 | Biol. Psychiatry 2011 Feb 69: 288-94 |
| PMID | 21035786 |
| Title | cAMP response element binding protein phosphorylation in nucleus accumbens underlies sustained recovery of sensorimotor gating following repeated D?-like receptor agonist treatment in rats. |
| Abstract | Prepulse inhibition (PPI) is a cross-species measure of sensorimotor gating. PPI deficits are observed in humans and rats upon acute treatment with dopamine D?-like receptor agonists and in patients with schizophrenia. Repeated treatment with a D?-like agonist, however, reverses PPI deficits and increases cyclic adenosine monophosphate (CAMP) signaling in the nucleus accumbens (NAc). This study examined the short- and long-term effects on PPI of treatment with quinpirole and ropinirole, dopamine D?/D? receptor agonists, and the molecular mechanism by which they occur. PPI was assessed in adult male Sprague-Dawley rats following acute and chronic treatment with quinpirole or ropinirole and 1, 2, 3, and 4 weeks after termination of repeated ropinirole treatment. Finally, the effect of dominant negative mutant CAMP response element binding protein (CREB) overexpression in the NAc on PPI following chronic quinpirole treatment was assessed. Acute quinpirole produced dose-dependent PPI deficits, whereas ropinirole caused consistent PPI reduction at all but the highest dose. Repeated ropinirole treatment significantly increased PPI compared with acute treatment, and increased CREB phosphorylation in NAc neurons. Subsequent ropinirole challenge had no effect as long as 28 days later, at which time NAc CREB phosphorylation had normalized. Overexpression of dominant negative mutant CREB prevented PPI recovery induced by chronic quinpirole treatment. Chronic quinpirole or ropinirole treatment produces sustained PPI recovery; CREB activity in the NAc is required to induce PPI recovery but not to maintain it. The results suggest that transcriptional regulation by CREB mediates long-lasting changes occurring within NAc circuits to promote recovery of sensorimotor gating. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 137 | Cell. Mol. Neurobiol. 2011 Jan 31: 135-43 |
| PMID | 20838877 |
| Title | Downregulation of the cAMP/PKA pathway in PC12 cells overexpressing NCS-1. |
| Abstract | It is well known that dopamine imbalances are associated with many psychiatric disorders and that the dopaminergic receptor D? is the main target of antipsychotics. Recently it was shown that levels of two proteins implicated in dopaminergic signaling, Neuronal calcium sensor-1 (NCS-1) and DARPP-32, are altered in the prefrontal cortex (PFC) of both schizophrenic and bipolar disorder patients. NCS-1, which inhibits D? internalization, is upregulated in the PFC of both patients. DARPP-32, which is a downstream effector of dopamine signaling, integrates the pathways of several neurotransmitters and is downregulated in the PFC of both patients. Here, we used PC12 cells stably overexpressing NCS-1 (PC12-NCS-1 cells) to address the function of this protein in DARPP-32 signaling pathway in vitro. PC12-NCS-1 cells displayed downregulation of the CAMP/PKA pathway, with decreased levels of CAMP and phosphorylation of CREB at Ser133. We also observed decreased levels of total and phosphorylated DARPP-32 at Thr34. However, these cells did not show alterations in the levels of D? and phosphorylation of DARPP-32 at Thr75. These results indicate that NCS-1 modulates PKA/CAMP signaling pathway. Identification of the cellular mechanisms linking NCS-1 and DARPP-32 may help in the understanding the signaling machinery with potential to be turned into targets for the treatment of schizophrenia and other debilitating psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 138 | Int. J. Dev. Neurosci. 2011 May 29: 215-23 |
| PMID | 21345366 |
| Title | Prefrontal cortical network connections: key site of vulnerability in stress and schizophrenia. |
| Abstract | The symptoms of schizophrenia involve profound dysfunction of the prefrontal cortex (PFC). PFC networks create our "mental sketch pad", and PFC dysfunction contributes to symptoms such as cognitive deficits, thought disorder, delusions and hallucinations. Neuropathological studies of schizophrenia have shown marked loss of dendritic spines in deep layer III, the sublayer where PFC microcircuits reside. The microcircuits consist of recurrent excitatory pyramidal cell networks that interconnect on spines, and excite each other via NMDA receptor signaling. The pyramidal cell persistent firing is sculpted by lateral inhibition from GABAergic basket and chandelier cells, thus creating tuned, persistent firing needed for accurate representational knowledge (i.e., working memory). The strength of pyramidal cell network connections is markedly and flexibly altered by intracellular signaling pathways in dendritic spines, a process called dynamic network connectivity (DNC). DNC proteins such as HCN channels are concentrated on dendritic spines in deep layer III. Under optimal conditions, network inputs to pyramidal cells are strengthened by noradrenergic alpha-2A inhibition of CAMP-HCN channel signaling, and sculpted by dopamine D1-CAMP-HCN channel weakening of inappropriate inputs. However, with stress exposure, high levels of CAMP-HCN channel signaling produces a collapse in network firing. With chronic stress exposure, spines reduce in size and are lost, and this process involves increased PKC signaling. Importantly, molecules that normally strengthen PFC networks connections and/or reverse the stress response, are often genetically altered in schizophrenia. As exposure to stress is a key factor in the precipitation of schizophrenic symptoms, these dysregulated signaling pathways in deep layer III may interact with already vulnerable circuitry to cause spine loss and the descent into illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 139 | Cell. Mol. Neurobiol. 2011 Jan 31: 135-43 |
| PMID | 20838877 |
| Title | Downregulation of the cAMP/PKA pathway in PC12 cells overexpressing NCS-1. |
| Abstract | It is well known that dopamine imbalances are associated with many psychiatric disorders and that the dopaminergic receptor D? is the main target of antipsychotics. Recently it was shown that levels of two proteins implicated in dopaminergic signaling, Neuronal calcium sensor-1 (NCS-1) and DARPP-32, are altered in the prefrontal cortex (PFC) of both schizophrenic and bipolar disorder patients. NCS-1, which inhibits D? internalization, is upregulated in the PFC of both patients. DARPP-32, which is a downstream effector of dopamine signaling, integrates the pathways of several neurotransmitters and is downregulated in the PFC of both patients. Here, we used PC12 cells stably overexpressing NCS-1 (PC12-NCS-1 cells) to address the function of this protein in DARPP-32 signaling pathway in vitro. PC12-NCS-1 cells displayed downregulation of the CAMP/PKA pathway, with decreased levels of CAMP and phosphorylation of CREB at Ser133. We also observed decreased levels of total and phosphorylated DARPP-32 at Thr34. However, these cells did not show alterations in the levels of D? and phosphorylation of DARPP-32 at Thr75. These results indicate that NCS-1 modulates PKA/CAMP signaling pathway. Identification of the cellular mechanisms linking NCS-1 and DARPP-32 may help in the understanding the signaling machinery with potential to be turned into targets for the treatment of schizophrenia and other debilitating psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 140 | Genet. Mol. Res. 2012 -1 11: 725-30 |
| PMID | 22576830 |
| Title | BDNF and DARPP-32 genes are not risk factors for schizophrenia in the Malay population. |
| Abstract | A number of studies have pointed to the association of BDNF (brain-derived neurotrophic factor) and DARPP-32 (dopamine- and CAMP-regulated phosphoprotein, 32 kDa) with schizophrenia. The purpose of this study was to determine whether these two genes are involved in the pathogenesis of schizophrenia in the Malay population. Two single nucleotide polymorphisms Val66Met of BDNF, -2036C>G and g.1238delG of DARPP-32 were genotyped in the Malay population in 200 patients with schizophrenia and 256 healthy controls. Analysis of allele and genotype frequencies in these two groups revealed no significant association of BDNF or DARPP-32 polymorphisms with schizophrenia in Malays. This is the first such association study in the Malay population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 141 | Neuron 2012 Oct 76: 223-39 |
| PMID | 23040817 |
| Title | Neuromodulation of thought: flexibilities and vulnerabilities in prefrontal cortical network synapses. |
| Abstract | This review describes unique neuromodulatory influences on working memory prefrontal cortical (PFC) circuits that coordinate cognitive strength with arousal state. Working memory arises from recurrent excitation within layer III PFC pyramidal cell NMDA circuits, which are afflicted in aging and schizophrenia. Neuromodulators rapidly and flexibly alter the efficacy of these synaptic connections, while leaving the synaptic architecture unchanged, a process called dynamic network connectivity (DNC). Increases in calcium-CAMP signaling open ion channels in long, thin spines, gating network connections. Inhibition of calcium-CAMP signaling by stimulating ?2A-adrenoceptors on spines strengthens synaptic efficacy and increases network firing, whereas optimal stimulation of dopamine D1 receptors sculpts network inputs to refine mental representation. Generalized increases in calcium-CAMP signaling during fatigue or stress disengage dlPFC recurrent circuits, reduce firing and impair top-down cognition. Impaired DNC regulation contributes to age-related cognitive decline, while genetic insults to DNC proteins are commonly linked to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 142 | Neurosci. Lett. 2012 Sep 525: 1-6 |
| PMID | 22884617 |
| Title | Comparison of cAMP-specific phosphodiesterase mRNAs distribution in mouse and rat brain. |
| Abstract | There are eleven families of phosphodiesterases that regulate cellular levels of cyclic nucleotides by degradation of CAMP or cGMP. Knowledge of the expression sites of different PDE genes in brain is of special importance for studies on development of specific inhibitors considering that, for example, PDE4 inhibitor treatments exhibit profound anti-inflammatory effects. To address possible species differences we examined the expression of mRNAs coding for the CAMP specific PDE4 and PDE7 families since inhibitors have been used in clinic for schizophrenia, mood disorders, cognition and inflammatory diseases treatment. We have compared the expression of these PDEs in mouse brain by in situ hybridization histochemistry in comparison with rat brain and found that their neuroanatomical distribution differs in a few areas. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 143 | Yale J Biol Med 2012 Mar 85: 45-58 |
| PMID | 22461743 |
| Title | Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale. |
| Abstract | The prefrontal cortex (PFC) is among the most evolved brain regions, contributing to our highest order cognitive abilities. It regulates behavior, thought, and emotion using working memory. Many cognitive disorders involve impairments of the PFC. A century of discoveries at Yale Medical School has revealed the neurobiology of PFC cognitive functions, as well as the molecular needs of these circuits. This work has led to the identification of therapeutic targets to treat cognitive disorders. Recent research has found that the noradrenergic ?2A agonist guanfacine can improve PFC function by strengthening PFC network connections via inhibition of CAMP-potassium channel signaling in postsynaptic spines. Guanfacine is now being used to treat a variety of PFC cognitive disorders, including Tourette's Syndrome and Attention Deficit Hyperactivity Disorder (ADHD). This article reviews the history of Yale discoveries on the neurobiology of PFC working memory function and the identification of guanfacine for treating cognitive disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 144 | Mol. Psychiatry 2012 Sep 17: 887-905 |
| PMID | 22584867 |
| Title | Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction. |
| Abstract | We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein-coupled receptor signaling and CAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European American and one African American, increasing overlap, reproducibility and consistency of findings from single-nucleotide polymorphisms to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Finally, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 145 | Hum. Mol. Genet. 2012 Jun 21: 2779-92 |
| PMID | 22422769 |
| Title | DISC1 variants 37W and 607F disrupt its nuclear targeting and regulatory role in ATF4-mediated transcription. |
| Abstract | Disrupted-In-schizophrenia 1 (DISC1), a strong genetic candidate for psychiatric illness, encodes a multicompartmentalized molecular scaffold that regulates interacting proteins with key roles in neurodevelopment and plasticity. Missense DISC1 variants are associated with the risk of mental illness and with brain abnormalities in healthy carriers, but the underlying mechanisms are unclear. We examined the effect of rare and common DISC1 amino acid substitutions on subcellular targeting. We report that both the rare putatively causal variant 37W and the common variant 607F independently disrupt DISC1 nuclear targeting in a dominant-negative fashion, predicting that DISC1 nuclear expression is impaired in 37W and 607F carriers. In the nucleus, DISC1 interacts with the transcription factor Activating Transcription Factor 4 (ATF4), which is involved in the regulation of cellular stress responses, emotional behaviour and memory consolidation. At basal CAMP levels, wild-type DISC1 inhibits the transcriptional activity of ATF4, an effect that is weakened by both 37W and 607F independently, most likely as a consequence of their defective nuclear targeting. The common variant 607F additionally reduces DISC1/ATF4 interaction, which likely contributes to its weakened inhibitory effect. We also demonstrate that DISC1 modulates transcriptional responses to endoplasmic reticulum stress, and that this modulatory effect is ablated by 37W and 607F. By showing that DISC1 amino acid substitutions associated with psychiatric illness affect its regulatory function in ATF4-mediated transcription, our study highlights a potential mechanism by which these variants may impact on transcriptional events mediating cognition, emotional reactivity and stress responses, all processes of direct relevance to psychiatric illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 146 | Neuropharmacology 2012 Mar 62: 1182-90 |
| PMID | 21856317 |
| Title | Selective phosphodiesterase inhibitors improve performance on the ED/ID cognitive task in rats. |
| Abstract | A number of selective phosphodiesterase (PDE) inhibitors have been demonstrated to improve learning in several rodent models of cognition. Given that schizophrenia is associated with impairments in frontal lobe-dependent cognitive functions (e.g., working memory and cognitive flexibility), we examined whether PDE inhibitors would attenuate cognitive deficits associated with schizophrenia. Persistent suppression of N-methyl-D-aspartate (NMDA) receptor function produces enduring structural changes in neocortical and limbic regions in a pattern similar to changes reported in schizophrenia. This similarity suggests that subchronic treatment with NMDA receptor antagonists (e.g., phencyclidine, PCP) may represent a useful preclinical model of neurobiological and related cognitive deficits associated with schizophrenia. We treated male Long-Evans rats with subchronic PCP (5 mg/kg, ip, BID, 7 d) or saline and then examined the effects of acute treatment with selected doses of PDE inhibitors that have been demonstrated to regulate both intracellular levels of CAMP and/or cGMP, and to improve cognitive function. We used an extradimensional-intradimensional (ED/ID) test of cognitive flexibility similar to those used in humans and non-human primates for assessing executive function. Subchronic treatment with PCP produced a selective impairment on ED shift (EDS) performance without significant impairment on any other discrimination problem when compared to saline-treated control animals. Selected doses of the four PDEIs evaluated (PDE2: BAY 60-7550; PDE4: rolipram; PDE5: sildenafil; PDE10A: papaverine) were able to significantly attenuate this cognitive deficit in EDS performance. This suggests that this rodent model of executive function was sensitive to pro-cognitive effects of intracellular effects resulting from PDE inhibition. Together, these data suggest that inhibition of PDE activity may represent valuable therapeutic targets to improve cognition associated with neuropsychiatric disorders that feature cognitive dysfunction as a key symptom. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 147 | Handb Exp Pharmacol 2012 -1 -1: 53-86 |
| PMID | 23129328 |
| Title | Dopamine receptor signaling and current and future antipsychotic drugs. |
| Abstract | All currently efficacious antipsychotic drugs have as part of their mechanism the ability to attenuate some or all of the signaling through the dopamine D(2) receptor. More recently, the dopamine D(1) receptor has been hypothesized to be a promising target for the treatment of negative and/or cognitive aspects of schizophrenia that are not improved by current antipsychotics. Although CAMP has been presumed to be the primary messenger for signaling through the dopamine receptors, the last decade has unveiled a complexity that has provided exciting avenues for the future discovery of antipsychotic drugs (APDs). We review the signaling mechanisms of currently approved APDs at dopamine D(2) receptors, and note that aripiprazole is a compound that is clearly differentiated from other approved drugs. Although aripiprazole has been postulated to cause dopamine stabilization due to its partial D(2) agonist properties, a body of literature suggests that an alternative mechanism, functional selectivity, is of primary importance. Finally, we review the signaling at dopamine D(1) receptors, and the idea that drugs that activate D(1) receptors may have use as APDs for improving negative and cognitive symptoms. We address the current state of drug discovery in the D(1) area and its relationship to novel signaling mechanisms. Our conclusion is that although the first APD targeting dopamine receptors was discovered more than a half-century ago, recent research advances offer the possibility that novel and/or improved drugs will emerge in the next decade. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 148 | Nihon Shinkei Seishin Yakurigaku Zasshi 2012 Feb 32: 9-18 |
| PMID | 22568121 |
| Title | [Pharmacology of antipsychotics at human dopamine D2 and D3 receptors]. |
| Abstract | Aripiprazole is a dopamine D/D3 and serotonin 5-HT1A receptor partial agonist which is approved for treatment of schizophrenia. We evaluated the pharmacological properties of aripiprazole, dopamine D2 receptor partial agonists and antipsychotics using forskolin-stimulated CAMP accumulation in cells expressing human dopamine D2 and D3 receptors. In cells expressing high densities of D2 receptor with high sensitivity for dopamine, the maximal agonist effects of partial agonists were higher than in cells expressing low densities of D2 receptor with low sensitivity for dopamine. Aripiprazole's intrinsic activities at D2 and D9 receptors were lower than those observed with partial agonists (terguride, bifeprunox, OPC-4392 and (-)-3-PPP), which demonstrated clinically suboptimal improvement of positive symptoms of schizophrenia patients, and higher than that of SDZ 208-912, which demonstrated incidence of extrapyramidal symptoms similar to haloperidol. Aripiprazole's appropriate intrinsic activities at D2 and D: receptors may contribute to desired results in a clinical profile. Antipsychotics (risperidone, olanzapine, amisulpride, sulpiride and perphenazine) which displayed antidepressive effects in schizophrenia patients behaved as preferential antagonists in cells expressing D2 receptors compared to cells expressing D3 receptors. Preferential antagonism at dopamine D2 receptors may play a role in the antidepressive effects of these antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 149 | Schizophr. Res. 2012 Jul 138: 280-4 |
| PMID | 22537567 |
| Title | An odor-specific threshold deficit implicates abnormal cAMP signaling in youths at clinical risk for psychosis. |
| Abstract | While olfactory deficits have been reported in schizophrenia and youths at-risk for psychosis, few studies have linked these deficits to current pathophysiological models of the illness. There is evidence that disrupted cyclic adenosine 3',5'-monophosphate (CAMP) signaling may contribute to schizophrenia pathology. As CAMP mediates olfactory signal transduction, the degree to which this disruption could manifest in olfactory impairment was ascertained. Odor-detection thresholds to two odorants that differ in the degree to which they activate intracellular CAMP were assessed in clinical risk and low-risk participants. Birhinal assessments of odor-detection threshold sensitivity to lyral and citralva were acquired in youths experiencing prodromal symptoms (n=17) and controls at low risk for developing psychosis (n=15). Citralva and lyral are odorants that differ in CAMP activation; citralva is a strong CAMP activator and lyral is a weak CAMP activator. The overall group-by-odor interaction was statistically significant. At-risk youths showed significantly reduced odor detection thresholds for lyral, but showed intact detection thresholds for citralva. This odor-specific threshold deficit was uncorrelated with deficits in odor identification or discrimination, which were also present. ROC curve analysis revealed that olfactory performance correctly classified at-risk and low-risk youths with greater than 97% accuracy. This study extends prior findings of an odor-specific hyposmia implicating CAMP-mediated signal transduction in schizophrenia and unaffected first-degree relatives to include youths at clinical risk for developing the disorder. These results suggest that dysregulation of CAMP signaling may be present during the psychosis prodrome. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 150 | J. Mol. Neurosci. 2012 Jul 47: 470-4 |
| PMID | 22367616 |
| Title | Association between a casein kinase 1 ? gene polymorphism and schizophrenia in a Chinese Han population. |
| Abstract | The casein kinase 1 (Csnk1) family of serine/threonine kinases regulates dopamine receptor (DR) signaling by phosphorylating the 32-kDa dopamine- and CAMP-regulated phosphoprotein DARPP-32, leading to inhibition of protein phosphatase 1 and a shift in the phosphorylation state of many downstream proteins. By modulating DR-activated phosphorylation cascades, Csnk1 plays a central role in neuropsychiatric disorders and modulates the stimulant response to amphetamine. No published study, however, has established a correlation between Csnk1 gene polymorphisms and schizophrenia. We genotyped the rs135745C/G polymorphism of the Csnk1? gene in 384 schizophrenic patients and 502 healthy controls drawn from the Chinese Han population. There were significantly higher CG and CC genotype frequencies in schizophrenic patients compared to control subjects (CG, p?=?0.0086, odds ratio (OR)?=?1.477, 95% confidence interval (CI), 1.103-1.978; CC, p?=?0.0431, OR?=?2.571; 95% CI, 0.998-6.624). The C allele frequency was also higher in the schizophrenics (p?=?0.0022; OR?=?1.474; 95% CI, 1.149-1.891). In the dominant model, subjects with genotypes CC or CG were at greater risk for schizophrenia (p?=?0.0032; OR?=?1.532; 95% CI, 1.153-2.037), suggesting that a genetic variant in the Csnk1? gene significantly enhances the probability of schizophrenia in the Chinese Han population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 151 | Neuropharmacology 2012 Jun 62: 2184-91 |
| PMID | 22300836 |
| Title | Heterocomplex formation of 5-HT2A-mGlu2 and its relevance for cellular signaling cascades. |
| Abstract | Dopamine, serotonin and glutamate play a role in the pathophysiology of schizophrenia. In the brain a functional crosstalk between the serotonin receptor 5-HT(2A) and the metabotropic glutamate receptor mGlu(2) has been demonstrated. Such a crosstalk may be mediated indirectly through neuronal networks or directly by receptor oligomerization. A direct link of the 5-HT(2A)-mGlu(2) heterocomplex formation to receptor function, i.e. to intracellular signaling, has not been fully demonstrated yet. Here we confirm the formation of 5-HT(2A)-mGlu(2) heterocomplexes using quantitative Snap/Clip-tag based HTRF methods. Additionally, mGlu(2) formed complexes with 5-HT(2B) and mGlu(5) but not 5-HT(2C) indicating that complex formation is not specific to the 5-HT(2A)-mGlu(2) pair. We studied the functional consequences of the 5-HT(2A)-mGlu(2) heterocomplex addressing cellular signaling pathways. Co-expression of receptors in HEK-293 cells had no relevant effects on signaling mediated by the individual receptors when mGlu(2) agonists, antagonists and PAMs, or 5-HT(2A) hallucinogenic and non-hallucinogenic agonists and antagonists were used. Hallucinogenic 5-HT(2A) agonists induced signaling through G(q/11), but not G(i) and thus did not lead to modulation of intracellular CAMP levels. In membranes of the medial prefrontal cortex [(3)H]-LY341495 binding competition of mGlu(2/3) agonist LY354740 was not influenced by 2,5-dimethoxy-4-iodoamphetamine (DOI). Taken together, the formation of GPCR heterocomplexes does not necessarily translate into second messenger effects. These results do not put into question the well-documented functional cross-talk of the two receptors in the brain, but do challenge the biological relevance of the 5-HT(2A)-mGlu(2) heterocomplex. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 152 | Neuropsychopharmacology 2012 Mar 37: 896-905 |
| PMID | 22048463 |
| Title | Abnormal activity of the MAPK- and cAMP-associated signaling pathways in frontal cortical areas in postmortem brain in schizophrenia. |
| Abstract | Recent evidence suggests that schizophrenia may result from alterations of integration of signaling mediated by multiple neurotransmitter systems. Abnormalities of associated intracellular signaling pathways may contribute to the pathophysiology of schizophrenia. Proteins and phospho-proteins comprising mitogen activated protein kinase (MAPK) and 3'-5'-cyclic adenosine monophosphate (CAMP)-associated signaling pathways may be abnormally expressed in the anterior cingulate (ACC) and dorsolateral prefrontal cortex (DLPFC) in schizophrenia. Using western blot analysis we examined proteins of the MAPK- and CAMP-associated pathways in these two brain regions. Postmortem samples were used from a well-characterized collection of elderly patients with schizophrenia (ACC=36, DLPFC=35) and a comparison (ACC=33, DLPFC=31) group. Near-infrared intensity of IR-dye labeled secondary antisera bound to targeted proteins of the MAPK- and CAMP-associated signaling pathways was measured using LiCor Odyssey imaging system. We found decreased expression of Rap2, JNK1, JNK2, PSD-95, and decreased phosphorylation of JNK1/2 at T183/Y185 and PSD-95 at S295 in the ACC in schizophrenia. In the DLPFC, we found increased expression of Rack1, Fyn, Cdk5, and increased phosphorylation of PSD-95 at S295 and NR2B at Y1336. MAPK- and CAMP-associated molecules constitute ubiquitous intracellular signaling pathways that integrate extracellular stimuli, modify receptor expression and function, and regulate cell survival and neuroplasticity. These data suggest abnormal activity of the MAPK- and CAMP-associated pathways in frontal cortical areas in schizophrenia. These alterations may underlie the hypothesized hypoglutamatergic function in this illness. Together with previous findings, these data suggest that abnormalities of intracellular signaling pathways may contribute to the pathophysiology of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 153 | Psychopharmacology (Berl.) 2012 Feb 219: 1065-79 |
| PMID | 21833500 |
| Title | Phosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/DARPP-32 signaling cascade in frontal cortex. |
| Abstract | Alteration of dopamine neurotransmission in the prefrontal cortex, especially hypofunction of dopamine D1 receptors, contributes to psychotic symptoms and cognitive deficit in schizophrenia. D1 receptors signal through the CAMP/PKA second messenger cascade, which is modulated by phosphodiesterase (PDE) enzymes that hydrolyze and inactivate cyclic nucleotides. Though several PDEs are expressed in cortical neurons, the PDE4 enzyme family (PDE4A-D) has been implicated in the control of cognitive function. The best studied isoform, PDE4B, interacts with a schizophrenia susceptibility factor, disrupted in schizophrenia 1 (DISC1). We explore the control of mouse frontal cortex dopamine D1 receptor signaling and associated behavior by PDE4. Inhibition of PDE4 by rolipram induced activation of CAMP/PKA signaling in cortical slices and in vivo, leading to the phosphorylation of DARPP-32 and other postsynaptic and presynaptic PKA-substrates. Rolipram also enhanced DARPP-32 phosphorylation invoked by D1 receptor activation. Immunohistochemical studies demonstrated PDE4A, PDE4B, and PDE4D expression in DARPP-32-positive neurons in layer VI of frontal cortex, most likely in D1 receptor-positive, glutamatergic corticothalamic pyramidal neurons. Furthermore, the ability of rolipram treatment to improve the performance of mice in a sensorimotor gating test was DARPP-32-dependent. PDE4, which is co-expressed with DARPP-32 in D1 receptor-positive cortical pyramidal neurons in layer VI, modulates the level of D1 receptor signaling and DARPP-32 phosphorylation in the frontal cortex, likely influencing cognitive function. These biochemical and behavioral actions of PDE4 inhibitors may contribute to the hypothesized antipsychotic actions of this class of compounds. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 154 | Neuropharmacology 2012 Mar 62: 1252-62 |
| PMID | 21376063 |
| Title | Synergistic interactions between PDE4B and GSK-3: DISC1 mutant mice. |
| Abstract | Disrupted-In-schizophrenia-1 (DISC1) is a strong genetic risk factor associated with psychiatric disorders. Two distinct mutations in the second exon of the DISC1 gene (Q31L and L100P) lead to either depression- or schizophrenia-like behavior in mice. Both phosphodiesterase-4B (PDE4B) and glycogen synthase kinase-3 (GSK-3) have common binding sites on N-terminal region of DISC1 and are implicated into etiology of schizophrenia and depression. It is not known if PDE4B and GSK-3 could converge signals in the cell via DISC1 at the same time. The purpose of the present study was to assess whether rolipram (PDE4 inhibitor) might synergize with TDZD-8 (GSK-3 blocker) to produce antipsychotic effects at low doses on the DISC1-L100P genetic model. Indeed, combined treatment of DISC1-L100P mice with rolipram (0.1 mg/kg) and TDZD-8 (2.5 mg/kg) in sub-threshold doses corrected their Pre-Pulse Inhibition (PPI) deficit and hyperactivity, without any side effects at these doses. We have suggested that rolipram-induced increase of CAMP level might influence GSK-3 function and, hence the efficacy of TDZD-8. Our second goal was to estimate how DISC1-Q31L with reduced PDE4B activity, and therefore mimicking rolipram-induced conditions, could alter pharmacological response to TDZD-8, GSK-3 activity and its interaction with DISC1. DISC1-Q31L mutants showed increased sensitivity to GSK-3 inhibitor compare to DISC1-L100P mice. TDZD-8 (2.5 mg/kg) was able to correct PPI deficit, reduce immobility in the forced swim test (FST) and increased social motivation/novelty. In parallel, biochemical analysis revealed significantly reduced binding of GSK-3 to the mutated DISC1-Q31L and increased enzymatic activity of GSK-3. Taken together, genetic variations in DISC1 influence formation of biochemical complex with PDE4 and GSK-3 and strength the possibility of synergistic interactions between these proteins. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 155 | J. Mol. Neurosci. 2012 Jul 47: 470-4 |
| PMID | 22367616 |
| Title | Association between a casein kinase 1 ? gene polymorphism and schizophrenia in a Chinese Han population. |
| Abstract | The casein kinase 1 (Csnk1) family of serine/threonine kinases regulates dopamine receptor (DR) signaling by phosphorylating the 32-kDa dopamine- and CAMP-regulated phosphoprotein DARPP-32, leading to inhibition of protein phosphatase 1 and a shift in the phosphorylation state of many downstream proteins. By modulating DR-activated phosphorylation cascades, Csnk1 plays a central role in neuropsychiatric disorders and modulates the stimulant response to amphetamine. No published study, however, has established a correlation between Csnk1 gene polymorphisms and schizophrenia. We genotyped the rs135745C/G polymorphism of the Csnk1? gene in 384 schizophrenic patients and 502 healthy controls drawn from the Chinese Han population. There were significantly higher CG and CC genotype frequencies in schizophrenic patients compared to control subjects (CG, p?=?0.0086, odds ratio (OR)?=?1.477, 95% confidence interval (CI), 1.103-1.978; CC, p?=?0.0431, OR?=?2.571; 95% CI, 0.998-6.624). The C allele frequency was also higher in the schizophrenics (p?=?0.0022; OR?=?1.474; 95% CI, 1.149-1.891). In the dominant model, subjects with genotypes CC or CG were at greater risk for schizophrenia (p?=?0.0032; OR?=?1.532; 95% CI, 1.153-2.037), suggesting that a genetic variant in the Csnk1? gene significantly enhances the probability of schizophrenia in the Chinese Han population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 156 | J. Mol. Neurosci. 2012 Jul 47: 470-4 |
| PMID | 22367616 |
| Title | Association between a casein kinase 1 ? gene polymorphism and schizophrenia in a Chinese Han population. |
| Abstract | The casein kinase 1 (Csnk1) family of serine/threonine kinases regulates dopamine receptor (DR) signaling by phosphorylating the 32-kDa dopamine- and CAMP-regulated phosphoprotein DARPP-32, leading to inhibition of protein phosphatase 1 and a shift in the phosphorylation state of many downstream proteins. By modulating DR-activated phosphorylation cascades, Csnk1 plays a central role in neuropsychiatric disorders and modulates the stimulant response to amphetamine. No published study, however, has established a correlation between Csnk1 gene polymorphisms and schizophrenia. We genotyped the rs135745C/G polymorphism of the Csnk1? gene in 384 schizophrenic patients and 502 healthy controls drawn from the Chinese Han population. There were significantly higher CG and CC genotype frequencies in schizophrenic patients compared to control subjects (CG, p?=?0.0086, odds ratio (OR)?=?1.477, 95% confidence interval (CI), 1.103-1.978; CC, p?=?0.0431, OR?=?2.571; 95% CI, 0.998-6.624). The C allele frequency was also higher in the schizophrenics (p?=?0.0022; OR?=?1.474; 95% CI, 1.149-1.891). In the dominant model, subjects with genotypes CC or CG were at greater risk for schizophrenia (p?=?0.0032; OR?=?1.532; 95% CI, 1.153-2.037), suggesting that a genetic variant in the Csnk1? gene significantly enhances the probability of schizophrenia in the Chinese Han population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 157 | Neuroscience 2013 Sep 247: 164-74 |
| PMID | 23727510 |
| Title | Human endogenous retrovirus W family envelope gene activates the small conductance Ca2+-activated K+ channel in human neuroblastoma cells through CREB. |
| Abstract | Numerous studies have shown that human endogenous retrovirus W family (HERV-W) envelope gene (env) is related to various diseases but the underlying mechanism has remained poorly understood. Our previous study showed that there was abnormal expression of HERV-W env in sera of patients with schizophrenia. In this paper, we reported that overexpression of the HERV-W env elevated the levels of small conductance Ca(2+)-activated K(+) channel protein 3 (SK3) in human neuroblastoma cells. Using a luciferase reporter system and RNA interference method, we found that functional CAMP response element site was required for the expression of SK3 triggered by HERV-W env. In addition, it was also found that the SK3 channel was activated by HERV-W env. Further study indicated that CAMP response element-binding protein (CREB) was required for the activation of the SK3 channel. Thus, a novel signaling mechanism of how HERV-W env influences neuronal activity and contributes to mental illnesses such as schizophrenia was proposed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 158 | Mol. Psychiatry 2013 Aug 18: 898-908 |
| PMID | 23587879 |
| Title | DISC1-ATF4 transcriptional repression complex: dual regulation of the cAMP-PDE4 cascade by DISC1. |
| Abstract | Disrupted-In-schizophrenia 1 (DISC1), a risk factor for major mental illnesses, has been studied extensively in the context of neurodevelopment. However, the role of DISC1 in neuronal signaling, particularly in conjunction with intracellular cascades that occur in response to dopamine, a neurotransmitter implicated in numerous psychiatric disorders, remains elusive. Previous data suggest that DISC1 interacts with numerous proteins that impact neuronal function, including activating transcription factor 4 (ATF4). In this study, we identify a novel DISC1 and ATF4 binding region in the genomic locus of phosphodiesterase 4D (PDE4D), a gene implicated in psychiatric disorders. We found that the loss of function of either DISC1 or ATF4 increases PDE4D9 transcription, and that the association of DISC1 with the PDE4D9 locus requires ATF4. We also show that PDE4D9 is increased by D1-type dopamine receptor dopaminergic stimulation. We demonstrate that the mechanism for this increase is due to DISC1 dissociation from the PDE4D locus in mouse brain. We further characterize the interaction of DISC1 with ATF4 to show that it is regulated via protein kinase A-mediated phosphorylation of DISC1 serine-58. Our results suggest that the release of DISC1-mediated transcriptional repression of PDE4D9 acts as feedback inhibition to regulate dopaminergic signaling. Furthermore, as DISC1 loss-of-function leads to a specific increase in PDE4D9, PDE4D9 itself may represent an attractive target for therapeutic approaches in psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 159 | Nat. Neurosci. 2013 Nov 16: 1627-36 |
| PMID | 24121738 |
| Title | Age-dependent regulation of synaptic connections by dopamine D2 receptors. |
| Abstract | Dopamine D2 receptors (D2R) are G protein-coupled receptors that modulate synaptic transmission and are important for various brain functions, including learning and working memory. Abnormal D2R signaling has been implicated in psychiatric disorders such as schizophrenia. Here we report a new function of D2R in dendritic spine morphogenesis. Activation of D2R reduced spine number via GluN2B- and CAMP-dependent mechanisms in mice. Notably, this regulation occurred only during adolescence. During this period, D2R overactivation caused by mutations in the schizophrenia risk gene Dtnbp1 led to spine deficiency, dysconnectivity in the entorhinal-hippoCAMPal circuit and impairment of spatial working memory. Notably, these defects could be ameliorated by D2R blockers administered during adolescence. Our findings suggest an age-dependent function of D2R in spine development, provide evidence that D2R dysfunction during adolescence impairs neuronal circuits and working memory, and indicate that adolescent interventions to prevent aberrant D2R activity protect against cognitive impairment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 160 | Cell. Signal. 2013 Oct 25: 2060-8 |
| PMID | 23770287 |
| Title | Rit subfamily small GTPases: regulators in neuronal differentiation and survival. |
| Abstract | Ras family small GTPases serve as binary molecular switches to regulate a broad array of cellular signaling cascades, playing essential roles in a vast range of normal physiological processes, with dysregulation of numerous Ras-superfamily G-protein-dependent regulatory cascades underlying the development of human disease. However, the physiological function for many "orphan" Ras-related GTPases remain poorly characterized, including members of the Rit subfamily GTPases. Rit is the founding member of a novel branch of the Ras subfamily, sharing close homology with the neuronally expressed Rin and Drosophila Ric GTPases. Here, we highlight recent studies using transgenic and knockout animal models which have begun to elucidate the physiological roles for the Rit subfamily, including emerging roles in the regulation of neuronal morphology and cellular survival signaling, and discuss new genetic data implicating Rit and Rin signaling in disorders such as cancer, Parkinson's disease, autism, and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 161 | Sci Rep 2013 -1 3: 926 |
| PMID | 23378895 |
| Title | Group II metabotropic glutamate receptors modify N-methyl-D-aspartate receptors via Src kinase. |
| Abstract | Group II metabotropic glutamate receptors (mGluR2/3) have emerged as important targets for the treatment of schizophrenia. Since hypofunction of N-methyl-D-aspartate receptors (NMDARs) has also been implicated in the etiology of schizophrenia, we examined whether postsynaptic mGluR2/3 regulate NMDAR function. Activation of mGluR2/3 significantly decreased the ratio of AMPA-to-NMDA excitatory postsynaptic currents at Schaffer Collateral-CA1 synapses and enhanced the peak of NMDA-evoked currents in acutely isolated CA1 neurons. The mGluR2/3-mediated potentiation of NMDAR currents was selective for GluN2A-containing NMDARs and was mediated by the Src family kinase Src. Activation of mGluR2/3 inhibited the adenylyl cyclase-CAMP-PKA pathway and thereby activated Src by inhibiting its regulatory C-terminal Src kinase (Csk). We suggest a novel model of regulation of NMDARs by Gi/o-coupled receptors whereby inhibition of the CAMP-PKA pathway via mGluR2/3 activates Src kinase and potentiates GluN2A-containing NMDAR currents. This represents a potentially novel mechanism to correct the hypoglutamatergic state found in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 162 | Transl Psychiatry 2013 -1 3: e328 |
| PMID | 24301646 |
| Title | Role of disrupted in schizophrenia 1 (DISC1) in stress-induced prefrontal cognitive dysfunction. |
| Abstract | Recent genetic studies have linked mental illness to alterations in disrupted in schizophrenia 1 (DISC1), a multifunctional scaffolding protein that regulates cyclic adenosine monophosphate (CAMP) signaling via interactions with phosphodiesterase 4 (PDE4). High levels of CAMP during stress exposure impair function of the prefrontal cortex (PFC), a region gravely afflicted in mental illness. As stress can aggravate mental illness, genetic insults to DISC1 may worsen symptoms by increasing CAMP levels. The current study examined whether viral knockdown (KD) of the Disc1 gene in rat PFC increases susceptibility to stress-induced PFC dysfunction. Rats were trained in a spatial working memory task before receiving infusions of (a) an active viral construct that knocked down Disc1 in PFC (DISC1 KD group), (b) a 'scrambled' construct that had no effect on Disc1 (Scrambled group), or (c) an active construct that reduced DISC1 expression dorsal to PFC (Anatomical Control group). Data were compared with an unoperated Control group. Cognitive performance was assessed following mild restraint stress that had no effect on normal animals. DISC1 KD rats were impaired by 1??h restraint stress, whereas Scrambled, Control, and Anatomical Control groups were unaffected. Thus, knocking down Disc1 in PFC reduced the threshold for stress-induced cognitive dysfunction, possibly through disinhibited CAMP signaling at neuronal network synapses. These findings may explain why patients with DISC1 mutations may be especially vulnerable to the effects of stress. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 163 | J. Pharmacol. Exp. Ther. 2013 Oct 347: 57-68 |
| PMID | 23863695 |
| Title | Pharmacological profile of 2-bromoterguride at human dopamine D2, porcine serotonin 5-hydroxytryptamine 2A, and ?2C-adrenergic receptors, and its antipsychotic-like effects in rats. |
| Abstract | Dopaminergic, serotonergic, and adrenergic receptors are targets for therapeutic actions in schizophrenia. Dopamine D2 receptor partial agonists such as aripiprazole represent a treatment option for patients with this severe disorder. The ineffectiveness of terguride, another D2 receptor partial agonist, in treating schizophrenia was recently attributed to its considerably high intrinsic activity at D2 receptors. In this study, we used functional assays for recombinant D2 receptors and native 5-hydroxytryptamine 2A (5-HT2A), ?2C-adrenergic, and histamine H1 receptors to compare the pharmacological properties of terguride and three of its halogenated derivatives (2-chloro-, 2-bromo-, 2-iodoterguride) with those of aripiprazole. Subsequently, we studied the antidopaminergic effects of 2-bromoterguride using amphetamine-induced locomotion (AIL). Its influence on spontaneous behavior was tested in the open field. Extrapyramidal side effect (EPS) liability was evaluated by catalepsy test. In a guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTP?S) binding assay, 2-chloro-, 2-bromo-, and 2-iodoterguride produced intrinsic activities at human D2short (hD2S) receptors that were half as high as the intrinsic activity for terguride; aripiprazole lacked agonist activity. 2-Bromoterguride and aripiprazole activated D2S receptor-mediated inhibition of CAMP accumulation to the same extent; intrinsic activity was half as high as that of terguride. All compounds tested behaved as antagonists at human D2long/G?o (hD2L/G?o) receptors. Compared with aripiprazole, terguride and its derivatives displayed higher affinity at porcine 5-HT2A receptors and ?2C-adrenoceptors and lower affinity at H1 receptors. 2-Bromoterguride inhibited AIL and did not induce catalepsy in rats. Because of its in vitro and in vivo properties, 2-bromoterguride may be a strong candidate for the treatment of schizophrenia with a lower risk to induce EPS. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 164 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2013 Oct 46: 64-9 |
| PMID | 23778016 |
| Title | Genetic analysis of common variants in the CMYA5 (cardiomyopathy-associated 5) gene with schizophrenia. |
| Abstract | Recently, CMYA5 was suggested as a susceptibility gene for schizophrenia based on two independent studies utilizing different ethnic samples. We designed a case-control study to examine whether 21 SNPs contained within CMYA5 were associated with the disorder in a western Han Chinese sample comprised of 488 schizophrenia patients and 516 healthy control subjects. The allele distribution of SNPs rs7714250, rs16877135 and rs13158477 showed significant association with schizophrenia (Puncorrected=0.008, Puncorrected=0.04, and Puncorrected=0.009, respectively) as well as the genotype distribution in the Cochran-Armitage trend test (Puncorrected=0.008, Puncorrected=0.037 and Puncorrected=0.011, respectively). After Bonferroni correction, rs7714250 showed a trend of association with schizophrenia both in allele distribution (Pcorrected=0.088) and genotype distribution (Pcorrected=0.088). Furthermore, significant associations were found in several two-, three-, four-, and five-SNP tests of haplotype analyses. Replications of the association of CMYA5 with schizophrenia across various studies suggest that it is very likely a potential common schizophrenia-related gene worldwide. Functional studies correlating CMYA5 with DTNBP1 and PKA warrant further investigation of the molecular basis of this gene in relationship to the signal transduction pathway(s) underlying the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 165 | Psychiatry Clin. Neurosci. 2013 Apr 67: 154-9 |
| PMID | 23581866 |
| Title | Platelet and serum calcium and magnesium concentration in suicidal and non-suicidal schizophrenic patients. |
| Abstract | The main processes modulated by Ca and involved in the cause of schizophrenia are alteration in the dopamine and glutamate neurotransmitter system. Intracellular effects of Mg-ions are opposite to Ca-ions in competition at K-ion channels, in Na/K-ATP-ase activity, CAMP/cGMP concentration and Ca-ion currents in pre- and postsynaptic membranes. We conducted this research due to the incongruent results on Ca and Mg concentration that have been published until now and to determine platelet Mg concentration in suicidal and non-suicidal schizophrenic patients. A group of schizophrenic patients consisted of 23 patients with attempted suicide (S-SCH) and 48 patients without suicidal behavior (K-SCH) diagnosed according to ICD-10 diagnosis (F20.0) with or without intentional self-harm (X60-X84). The control group (K) included 99 healthy voluntary blood donors. The Mg and Ca concentration in platelets and serum was determined by atomic absorption spectrophotometry on the AAnalyst 200. Using one-way anova test and manifold application of the Student-Newman-Keuls post-hoc test we established that there were higher concentrations of platelet Mg (?mol/109 platelets) (P=0.009, F=4.89) and lower concentrations of serum Ca (mmol/L) (P<0.001, F=19.18) in the S-SCH group of patients and higher concentrations of platelet Ca/Mg ratio in the K-SCH group of patients (P=0.006, F=5.37). A higher Ca/Mg ratio in the platelets of non-suicidal patients confirms indirect higher Ca concentration. Higher Mg concentration in the platelets of suicidal patients, considered a Ca antagonist, may represent a compensatory attempt to restrain Ca activity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 166 | J. Biol. Chem. 2013 May 288: 15023-34 |
| PMID | 23576434 |
| Title | Role of SAP97 protein in the regulation of corticotropin-releasing factor receptor 1 endocytosis and extracellular signal-regulated kinase 1/2 signaling. |
| Abstract | The corticotropin-releasing factor (CRF) receptor 1 (CRFR1) is a target for the treatment of psychiatric diseases such as depression, schizophrenia, anxiety disorder, and bipolar disorder. The carboxyl-terminal tail of the CRFR1 terminates in a PDZ-binding motif that provides a potential site for the interaction of PSD-95/Discs Large/Zona Occludens 1 (PDZ) domain-containing proteins. In this study, we found that CRFR1 interacts with synapse-associated protein 97 (SAP97; also known as DLG1) by co-immunoprecipitation in human embryonic 293 (HEK 293) cells and cortical brain lysates and that this interaction is dependent upon an intact PDZ-binding motif at the end of the CRFR1 carboxyl-terminal tail. Similarly, we demonstrated that SAP97 is recruited to the plasma membrane in HEK 293 cells expressing CRFR1 and that mutation of the CRFR1 PDZ-binding motif results in the redistribution of SAP97 into the cytoplasm. Overexpression of SAP97 antagonized agonist-stimulated CRFR1 internalization, whereas single hairpin (shRNA) knockdown of endogenous SAP97 in HEK 293 cells resulted in increased agonist-stimulated CRFR1 endocytosis. CRFR1 was internalized as a complex with SAP97 resulting in the redistribution of SAP97 to endocytic vesicles. Overexpression or shRNA knockdown of SAP97 did not significantly affect CRFR1-mediated CAMP formation, but SAP97 knockdown did significantly attenuate CRFR1-stimulated ERK1/2 phosphorylation in a PDZ interaction-independent manner. Taken together, our studies show that SAP97 interactions with CRFR1 attenuate CRFR1 endocytosis and that SAP97 is involved in coupling G protein-coupled receptors to the activation of the ERK1/2 signaling pathway. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 167 | Mol Biosyst 2013 Mar 9: 386-97 |
| PMID | 23354020 |
| Title | Inhibition mechanism exploration of quinoline derivatives as PDE10A inhibitors by in silico analysis. |
| Abstract | As a potential target for the treatment of schizophrenia, the dual CAMP/cGMP hydrolyzing enzyme PDE10A has attracted a significant amount of attention. In the present work, the inhibition mechanism of 116 structurally diverse quinoline derivatives as PDE10A inhibitors was explored by 3D-QSAR, molecular docking and molecular dynamics (MD) simulations. The QSAR models based on the training set containing 88 molecules were established by using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The resultant optimum CoMSIA model showed strong predictability with a Q(2) of 0.497, an R(ncv)(2) of 0.964 and an R(pre)(2) of 0.885. Furthermore, there was good consistency between the CoMSIA model, docking and MD results. Our findings are: (1) bulky substituents at the 8-position and ring D increase the biological activity. (2) The areas around the 14-position and ring D are the electrostatic and hydrophobic sensitive regions. (3) H-bonds, ?-? stacking interactions and hydrophobic contacts are crucial in determining the binding affinity to PDE10A. (4) The six-membered heterocyclic group at ring D, especially a heterobenzene ring, containing the atom as an H-bond acceptor at the 18-position is essential to water-mediated H-bond networks and favorable in enhancing the inhibitory potency. These models and the derived information may help to provide better understanding of the interaction mechanism of PDE10A inhibitors and to facilitate lead optimization and novel inhibitors' design. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 168 | Phytother Res 2013 Dec 27: 1763-9 |
| PMID | 23348874 |
| Title | Prunella vulgaris attenuates prepulse inhibition deficit and attention disruption induced by MK-801 in mice. |
| Abstract | Prunella vulgaris var. lilacina is widely distributed in Korea, Japan, China, and Europe, and it has been traditionally used to treat inflammation or hypertension. In the present study, we investigated the effects of the ethanolic extract of the spikes of Prunella vulgaris var. lilacina (EEPV) on dizocilpine (MK-801)-induced schizophrenia-like phenotype behaviors such as the disruption of prepulse inhibition and attention deficits in mice. We also determined the effect of EEPV on MK-801-induced alterations in phosphorylated extracellular signal-regulated kinase, phosphorylated protein kinase B, phospho-glycogen synthase kinase 3-?, and phosphorylated CAMP response element-binding protein levels in the cortex and hippoCAMPus of mice. MK-801-induced prepulse inhibition deficits were ameliorated by the administration of EEPV, as shown in the acoustic startle response test. Furthermore, EEPV attenuated the MK-801-induced attention deficits in the water finding test. We also found that EEPV attenuated the increased phosphorylated extracellular signal-regulated kinase, phosphorylated protein kinase B, or phospho-glycogen synthase kinase 3-? levels induced by MK-801 in the cortex but not in the hippoCAMPus. These results suggest that EEPV could be useful for treating schizophrenia because EEPV ameliorates prepulse inhibition disruption and attention deficits induced by MK-801. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 169 | Int. J. Dev. Neurosci. 2013 May 31: 189-95 |
| PMID | 23313435 |
| Title | Postnatal maternal deprivation and pubertal stress have additive effects on dopamine D2 receptor and CaMKII beta expression in the striatum. |
| Abstract | The goal of this study was to determine whether two stressors commonly used to model aspects of neuropsychiatric disease in rats have an additive effect on striatal dopamine type 2 receptor (D2R) expression, a key player in the etiology of neuropsychiatric disease. Animals subjected to early postnatal stress show alterations in function of the dopaminergic system thought to be mediated by stress-induced glucocorticoid release. Subsequent stress during puberty is known to further impact the dopaminergic system and result in dopaminergic hyperactivity analogous to schizophrenia. We exposed rats to maternal deprivation (MD) during the second postnatal week, a time of active striatal development. A subset of these animals were then subjected to pubertal stress induced by immobilization. Both procedures are know to induce glucocorticoid release. At the conclusion of the MD protocol, we observed upregulation in the expression of D2R and of dopamine- and CAMP-regulated phosphoprotein 32-KD (DARPP-32; PPP1R1B), but not of D1R, calcium/calmodulin-dependent protein kinase II beta (CaMKII?), CaMKII? or neurokinin B (NKB). Animals exposed to pubertal stress showed upregulation in expression of both D2R and CaMKII?. Furthermore, rats previously exposed to MD showed a much greater upregulation in CaMKII? expression, than animals only exposed to pubertal stress. These results support the two-hit hypothesis, indicating that such stressors have an additive effect. The main targets appear to be the D2R and the CaMKII?, the latter being an important member of the DR signalling pathway, both of which are associated with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 170 | Biol. Psychiatry 2013 Jul 74: 113-21 |
| PMID | 23290496 |
| Title | Selective knockout of the casein kinase 2 in d1 medium spiny neurons controls dopaminergic function. |
| Abstract | Dopamine, crucial for the regulation of motor function and reward, acts through receptors mainly expressed in striatum as well as cortex. Dysregulation of dopaminergic signaling is associated with various neuropsychiatric disorders. Consequently, dopamine-regulating drugs are effectively used in treating these disorders, such as L-DOPA for Parkinson's disease, methylphenidate for attention-deficit/hyperactivity disorder, or antipsychotics for schizophrenia. As a result, there has been much interest in dissecting signaling networks in the two morphologically indistinguishable D1- and D2-receptor-expressing medium spiny neurons. Our previous results highlighted a role for casein kinase 2 (CK2) in the modulation of dopamine D1 receptor (D1R) signaling in cells. To study the importance of CK2 in vivo, we have selectively knocked out CK2, in either D1- or D2-medium spiny neurons (MSNs) and characterized the mice behaviorally and biochemically (n = 4-18). The D1-MSN knockout mice exhibited distinct behavioral phenotypes including novelty-induced hyperlocomotion and exploratory behavior, defective motor control, and motor learning. All of these behavioral traits are indicative of dysregulated dopamine signaling and the underlying mechanism appears to be an alteration of D1R signaling. In support of this hypothesis, D1R levels were upregulated in the knockout mice, as well as phosphorylation of DARPP-32 (dopamine- and cyclic adenosine monophosphate [CAMP]-regulated phospho-protein of 32 kDa), most of the behavioral phenotypes were abolished by the D1R antagonist, SCH23390, and the D2-MSN knockout mice displayed no obvious behavioral phenotype. A single kinase, CK2, in D1-MSNs significantly alters dopamine signaling, a finding that could have therapeutic implications for disorders characterized by dopamine imbalance such as Parkinson's disease, attention-deficit/hyperactivity disorder, and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 171 | Eur. J. Nucl. Med. Mol. Imaging 2013 Jan 40: 254-61 |
| PMID | 23160998 |
| Title | Human biodistribution and dosimetry of 18F-JNJ42259152, a radioligand for phosphodiesterase 10A imaging. |
| Abstract | Phosphodiesterase 10A (PDE10A) is a CAMP/cGMP-hydrolysing enzyme with a central role in striatal signalling and implicated in neuropsychiatric disorders such as Huntington's disease, Parkinson's disease, schizophrenia and addiction. We have developed a novel PDE10A PET ligand, (18)F-JNJ42259152, and describe here its human dynamic biodistribution, safety and dosimetry. Six male subjects (age range 23-67 years) underwent ten dynamic whole-body PET/CT scans over 6 h after bolus injection of 175.5 ± 9.4 MBq (18)F-JNJ42259152. Source organs were delineated on PET/CT and individual organ doses and effective dose were determined using the OLINDA software. F-JNJ42259152 was readily taken up by the brain and showed exclusive retention in the brain, especially in the striatum with good washout starting after 20 min. The tracer was cleared through both the hepatobiliary and the urinary routes. No defluorination was observed. Organ absorbed doses were largest for the gallbladder (239 ?Sv/MBq) and upper large intestine (138 ?Sv/MBq). The mean effective dose was 24.9 ± 4.1 ?Sv/MBq. No adverse events were encountered. In humans, (18)F-JNJ42259152 has an appropriate distribution, brain kinetics and safety. The estimated effective dose was within WHO class IIb with low interindividual variability. Therefore, the tracer is suitable for further kinetic evaluation in humans. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 172 | Neuropsychopharmacology 2013 Feb 38: 423-36 |
| PMID | 23011268 |
| Title | Disrupted-in-schizophrenia-1 Gln31Leu polymorphism results in social anhedonia associated with monoaminergic imbalance and reduction of CREB and ?-arrestin-1,2 in the nucleus accumbens in a mouse model of depression. |
| Abstract | Disrupted-in-schizophrenia-1 (DISC1) is associated with mental disorders, including major depression. We previously showed that DISC1-Q31L mutant mice have depression-like behaviors and can therefore be used to study neurobiological mechanisms of depression and antidepressant (AD) medication action. First, we found reduced levels of dopamine, serotonin and norepinephrine in the nucleus accumbens (NAC) of DISC1-Q31L mutants. Next, we assessed social-conditioned place preference as a reward-dependent task and the capacity of distinct ADs to correct impaired social behavior in DISC1-Q31L mice. Bupropion, but not fluoxetine or desipramine, was able to correct deficient social facilitation, social reward, and social novelty in DISC1-Q31L mutants, whereas all three ADs were able to improve social motivation and behavioral despair in DISC1-Q31L mutants. Furthermore, we sought to correlate social anhedonia with molecular and cellular features including dendritic spine density, ?-arrestin-1,2, and CAMP-response-element-binding protein (CREB) in the NAC as biomarkers related to depression and the DISC1 pathway. DISC1-Q31L mutants showed reduced levels of ?-arrestin-1,2, CREB, and spine density in the NAC, further supporting the construct validity of the genetic model. Bupropion induced the greatest effect on CREB in DISC1-Q31L mutants, whereas all studied ADs corrected the reduced levels of ?-arrestin-1,2 and modestly ameliorated deficient spine density in this brain region. Overall, we find neurobiological changes accompanying social anhedonia in the NAC of DISC1-Q31L mutant mice, consistent with a role for DISC1 in regulating social reward as an endophenotype of depression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 173 | Neuropharmacology 2013 Jan 64: 215-23 |
| PMID | 22750078 |
| Title | The novel phosphodiesterase 10A inhibitor THPP-1 has antipsychotic-like effects in rat and improves cognition in rat and rhesus monkey. |
| Abstract | Phosphodiesterase 10A (PDE10A) is a novel target for the treatment of schizophrenia that may address multiple symptomatic domains associated with this disorder. PDE10A is highly expressed in the brain and functions to metabolically inactivate the important second messengers CAMP and cGMP. Here we describe effects of a potent and orally bioavailable PDE10A inhibitor [2-(6-chloropyridin-3-yl)-4-(2-methoxyethoxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl](imidazo[1,5-a]pyridin-1-yl)methanone] (THPP-1) on striatal signaling pathways, in behavioral tests that predict antipsychotic potential, and assays that measure episodic-like memory in rat and executive function in rhesus monkey. THPP-1 exhibits nanomolar potency on the PDE10A enzyme, demonstrates excellent pharmacokinetic properties in multiple preclinical animal species, and is selective for PDE10A over other PDE families of enzymes. THPP-1 significantly increased phosphorylation of proteins in the striatum involved in synaptic plasticity, including the a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor (AMPA) GluR1 subunit, extracellular receptor kinase (ERK), and CAMP-response element binding protein (CREB). THPP-1 produced dose-dependent effects in preclinical assays predictive of antipsychotic activity including attenuation of MK-801-induced psychomotor activation and condition avoidance responding in rats. At similar plasma exposures, THPP-1 significantly increased object recognition memory in rat and attenuated a ketamine-induced deficit in the object retrieval detour task in rhesus monkey. These findings suggest that PDE10A inhibitors have the potential to impact multiple symptomatic domains of schizophrenia including positive symptoms and cognitive impairment. This article is part of a Special Issue entitled 'Cognitive Enhancers'. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 174 | Cereb. Cortex 2013 Jul 23: 1643-54 |
| PMID | 22693343 |
| Title | Constellation of HCN channels and cAMP regulating proteins in dendritic spines of the primate prefrontal cortex: potential substrate for working memory deficits in schizophrenia. |
| Abstract | schizophrenia associates with impaired prefrontal cortical (PFC) function and alterations in cyclic AMP (CAMP) signaling pathways. These include genetic insults to disrupted-in-schizophrenia (DISC1) and phosphodiesterases (PDE4s) regulating CAMP hydrolysis, and increased dopamine D1 receptor (D1R) expression that elevates CAMP. We used immunoelectron microscopy to localize DISC1, PDE4A, PDE4B, and D1R in monkey PFC and to view spatial interactions with hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that gate network inputs when opened by CAMP. Physiological interactions between PDE4s and HCN channels were tested in recordings of PFC neurons in monkeys performing a spatial working memory task. The study reveals a constellation of CAMP-related proteins (DISC1, PDE4A, and D1R) and HCN channels next to excitatory synapses and the spine neck in thin spines of superficial PFC, where working memory microcircuits interconnect and spine loss is most evident in schizophrenia. In contrast, channels in dendrites were distant from synapses and CAMP-related proteins, and were associated with endosomal trafficking. The data suggest that a CAMP signalplex is selectively positioned in the spines to gate PFC pyramidal cell microcircuits. Single-unit recordings confirmed physiological interactions between CAMP and HCN channels, consistent with gating actions. These data may explain why PFC networks are especially vulnerable to genetic insults that dysregulate CAMP signaling. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 175 | Psychiatry Clin. Neurosci. 2013 Apr 67: 154-9 |
| PMID | 23581866 |
| Title | Platelet and serum calcium and magnesium concentration in suicidal and non-suicidal schizophrenic patients. |
| Abstract | The main processes modulated by Ca and involved in the cause of schizophrenia are alteration in the dopamine and glutamate neurotransmitter system. Intracellular effects of Mg-ions are opposite to Ca-ions in competition at K-ion channels, in Na/K-ATP-ase activity, CAMP/cGMP concentration and Ca-ion currents in pre- and postsynaptic membranes. We conducted this research due to the incongruent results on Ca and Mg concentration that have been published until now and to determine platelet Mg concentration in suicidal and non-suicidal schizophrenic patients. A group of schizophrenic patients consisted of 23 patients with attempted suicide (S-SCH) and 48 patients without suicidal behavior (K-SCH) diagnosed according to ICD-10 diagnosis (F20.0) with or without intentional self-harm (X60-X84). The control group (K) included 99 healthy voluntary blood donors. The Mg and Ca concentration in platelets and serum was determined by atomic absorption spectrophotometry on the AAnalyst 200. Using one-way anova test and manifold application of the Student-Newman-Keuls post-hoc test we established that there were higher concentrations of platelet Mg (?mol/109 platelets) (P=0.009, F=4.89) and lower concentrations of serum Ca (mmol/L) (P<0.001, F=19.18) in the S-SCH group of patients and higher concentrations of platelet Ca/Mg ratio in the K-SCH group of patients (P=0.006, F=5.37). A higher Ca/Mg ratio in the platelets of non-suicidal patients confirms indirect higher Ca concentration. Higher Mg concentration in the platelets of suicidal patients, considered a Ca antagonist, may represent a compensatory attempt to restrain Ca activity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 176 | Cell. Signal. 2014 Sep 26: 1958-74 |
| PMID | 24815749 |
| Title | Mitotic activation of the DISC1-inducible cyclic AMP phosphodiesterase-4D9 (PDE4D9), through multi-site phosphorylation, influences cell cycle progression. |
| Abstract | In Rat-1 cells, the dramatic decrease in the levels of both intracellular cyclic 3'5' adenosine monophosphate (cyclic AMP; CAMP) and in the activity of CAMP-activated protein kinase A (PKA) observed in mitosis was paralleled by a profound increase in CAMP hydrolyzing phosphodiesterase-4 (PDE4) activity. The decrease in PKA activity, which occurs during mitosis, was attributable to PDE4 activation as the PDE4 selective inhibitor, rolipram, but not the phosphodiesterase-3 (PDE3) inhibitor, cilostamide, specifically ablated this cell cycle-dependent effect. PDE4 inhibition caused Rat-1 cells to move from S phase into G2/M more rapidly, to transit through G2/M more quickly and to remain in G1 for a longer period. Inhibition of PDE3 elicited no observable effects on cell cycle dynamics. Selective immunopurification of each of the four PDE4 sub-families identified PDE4D as being selectively activated in mitosis. Subsequent analysis uncovered PDE4D9, an isoform whose expression can be regulated by Disrupted-In-schizophrenia 1 (DISC1)/activating transcription factor 4 (ATF4) complex, as the sole PDE4 species activated during mitosis in Rat-1 cells. PDE4D9 becomes activated in mitosis through dual phosphorylation at Ser585 and Ser245, involving the combined action of ERK and an unidentified 'switch' kinase that has previously been shown to be activated by H2O2. Additionally, in mitosis, PDE4D9 also becomes phosphorylated at Ser67 and Ser81, through the action of MK2 (MAPKAPK2) and AMP kinase (AMPK), respectively. The multisite phosphorylation of PDE4D9 by all four of these protein kinases leads to decreased mobility (band-shift) of PDE4D9 on SDS-PAGE. PDE4D9 is predominantly concentrated in the perinuclear region of Rat-1 cells but with a fraction distributed asymmetrically at the cell margins. Our investigations demonstrate that the diminished levels of CAMP and PKA activity that characterise mitosis are due to enhanced CAMP degradation by PDE4D9. PDE4D9, was found to locate primarily not only in the perinuclear region of Rat-1 cells but also at the cell margins. We propose that the sequestration of PDE4D9 in a specific complex together with AMPK, ERK, MK2 and the H2O2-activatable 'switch' kinase allows for its selective multi-site phosphorylation, activation and regulation in mitosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 177 | Synapse 2014 Jun 68: 257-65 |
| PMID | 24615983 |
| Title | Phencyclidine rapidly decreases neuronal mRNA of brain-derived neurotrophic factor. |
| Abstract | Downregulation of brain-derived neurotrophic factor (BDNF), a member of neurotrophin family, has been implicated in psychiatric diseases including schizophrenia. However, detailed mechanisms of its reduction in patients with schizophrenia remain unclear. Here, using cultured cortical neurons, we monitored BDNF mRNA levels following acute application of phencyclidine [PCP; an N-methyl-d-aspartate (NMDA) receptor blocker], which is known to produce schizophrenia-like symptoms. We found that PCP rapidly caused a reduction in total amount of BDNF transcripts without effect on cell viability, while mRNA levels of nerve growth factor was intact. Actinomycin-D (ActD), an RNA synthesis inhibitor, decreased total BDNF mRNA levels similar to PCP, and coapplication of ActD with PCP did not show further reduction in BDNF mRNA compared with solo application of each drug. Among BDNF exons I, IV, and VI, the exon IV, which is positively regulated by neuronal activity, was highly sensitive to PCP. Furthermore, PCP inactivated CAMP response element-binding protein (CREB; a regulator of transcriptional activity of exon IV). The inactivation of CREB was also achieved by an inhibitor for Ca(2+) /calmodulin kinase II (CaMKII), although coapplication with PCP induced no further inhibition on the CREB activity. It is possible that PCP decreases BDNF transcription via blocking the NMDA receptor/CaMKII/CREB signaling. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 178 | Prog. Lipid Res. 2014 Jan 53: 1-17 |
| PMID | 24334113 |
| Title | Long-chain polyunsaturated fatty acids (LCPUFA) from genesis to senescence: the influence of LCPUFA on neural development, aging, and neurodegeneration. |
| Abstract | Many clinical and animal studies demonstrate the importance of long-chain polyunsaturated fatty acids (LCPUFA) in neural development and neurodegeneration. This review will focus on involvement of LCPUFA from genesis to senescence. The LCPUFA docosahexaenoic acid and arachidonic acid are important components of neuronal membranes, while eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid also affect cardiovascular health and inflammation. In neural development, LCPUFA deficiency can lead to severe disorders like schizophrenia and attention deficit hyperactivity disorder. Perinatal LCPUFA supplementation demonstrated beneficial effects in neural development in humans and rodents resulting in improved cognition and sensorimotor integration. In normal aging, the effect of LCPUFA on prevention of cognitive impairment will be discussed. LCPUFA are important for neuronal membrane integrity and function, and also contribute in prevention of brain hypoperfusion. Cerebral perfusion can be compromised as result of obesity, cerebrovascular disease, hypertension, or diabetes mellitus type 2. Last, we will focus on the role of LCPUFA in most common neurodegenerative diseases like Alzheimer's disease and Parkinson's disease. These disorders are characterized by impaired cognition and connectivity and both clinical and animal supplementation studies have shown the potential of LCPUFA to decrease neurodegeneration and inflammation. This review shows that LCPUFA are essential throughout life. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 179 | Sci Pharm 2014 Sep 82: 453-81 |
| PMID | 25853062 |
| Title | Selective Phosphodiesterase 4B Inhibitors: A Review. |
| Abstract | Phosphodiesterase 4B (PDE4B) is a member of the phosphodiesterase family of proteins that plays a critical role in regulating intracellular levels of cyclic adenosine monophosphate (CAMP) by controlling its rate of degradation. It has been demonstrated that this isoform is involved in the orchestra of events which includes inflammation, schizophrenia, cancers, chronic obstructive pulmonary disease, contractility of the myocardium, and psoriatic arthritis. Phosphodiesterase 4B has constituted an interesting target for drug development. In recent years, a number of PDE4B inhibitors have been developed for their use as therapeutic agents. In this review, an up-to-date status of the inhibitors investigated for the inhibition of PDE4B has been given so that this rich source of structural information of presently known PDE4B inhibitors could be helpful in generating a selective and potent inhibitor of PDE4B. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 180 | J. Med. Chem. 2014 Nov 57: 9627-43 |
| PMID | 25384088 |
| Title | Discovery of 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (TAK-063), a highly potent, selective, and orally active phosphodiesterase 10A (PDE10A) inhibitor. |
| Abstract | A novel series of pyridazinone-based phosphodiesterase 10A (PDE10A) inhibitors were synthesized. Our optimization efforts using structure-based drug design (SBDD) techniques on the basis of the X-ray crystal structure of PDE10A in complex with hit compound 1 (IC50 = 23 nM; 110-fold selectivity over other PDEs) led to the identification of 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (27h). Compound 27h has potent inhibitory activity (IC50 = 0.30 nM), excellent selectivity (>15000-fold selectivity over other PDEs), and favorable pharmacokinetics, including high brain penetration, in mice. Oral administration of compound 27h to mice elevated striatal 3',5'-cyclic adenosine monophosphate (CAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) levels at 0.3 mg/kg and showed potent suppression of phencyclidine (PCP)-induced hyperlocomotion at a minimum effective dose (MED) of 0.3 mg/kg. Compound 27h (TAK-063) is currently being evaluated in clinical trials for the treatment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 181 | Mol. Pharmacol. 2014 Oct 86: 390-8 |
| PMID | 25057049 |
| Title | A role for picomolar concentrations of pregnenolone sulfate in synaptic activity-dependent Ca2+ signaling and CREB activation. |
| Abstract | Fast excitatory synaptic transmission that is contingent upon N-methyl d-aspartate receptor (NMDAR) function contributes to core information flow in the central nervous system and to the plasticity of neural circuits that underlie cognition. Hypoactivity of excitatory NMDAR-mediated neurotransmission is hypothesized to underlie the pathophysiology of schizophrenia, including the associated cognitive deficits. The neurosteroid pregnenolone (PREG) and its metabolites pregnenolone sulfate (PregS) and allopregnanolone in serum are inversely associated with cognitive improvements after oral PREG therapy, raising the possibility that brain neurosteroid levels may be modulated therapeutically. PregS is derived from PREG, the precursor of all neurosteroids, via a single sulfation step and is present at low nanomolar concentrations in the central nervous system. PregS, but not PREG, augments long-term potentiation and cognitive performance in animal models of learning and memory. In this report, we communicate the first observation that PregS, but not PREG, is a potent (EC50 ?2 pM) enhancer of intracellular Ca(2+) that is contingent upon neuronal activity, NMDAR-mediated synaptic activity, and L-type Ca(2+) channel activity. Low picomolar PregS similarly activates CAMP response element-binding protein (CREB) phosphorylation (within 10 minutes), an essential memory molecule, via an extracellular-signal-regulated kinase/mitogen-activated protein kinase signal transduction pathway. Taken together, the results are consistent with a novel biologic role for the neurosteroid PregS that acts at picomolar concentrations to intensify the intracellular response to glutamatergic signaling at synaptic but not extrasynaptic, NMDARs by differentially augmenting CREB activation. This provides a genomic signal transduction mechanism by which PregS could participate in memory consolidation of relevance to cognitive function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 182 | Biol. Psychiatry 2014 Sep 76: 476-85 |
| PMID | 24560582 |
| Title | Disrupted in schizophrenia 1 modulates medial prefrontal cortex pyramidal neuron activity through cAMP regulation of transient receptor potential C and small-conductance K+ channels. |
| Abstract | Disrupted in schizophrenia 1 (DISC1) is a protein implicated in schizophrenia, bipolar disorder, major depressive disorder, and autism. To date, most of research examining DISC1 function has focused on its role in neurodevelopment, despite its presence throughout life. DISC1 also regulates cyclic adenosine monophosphate (CAMP) signaling by increasing type 4 phosphodiesterase catabolism of CAMP when CAMP concentrations are high. In this study, we tested the hypothesis that DISC1, through its regulation of CAMP, modulates I-SK and I-TRPC channel-mediated ionic currents that we have shown previously to regulate the activity of mature prefrontal cortical pyramidal neurons. We used patch-clamp recordings in prefrontal cortical slices from adult rats in which DISC1 function was reduced in vivo by short hairpin RNA viral knockdown or in vitro by dialysis of DISC1 antibodies. We found that DISC1 disruption resulted in an increase of metabotropic glutamate receptor-induced intracellular calcium (Ca2+) waves, small-conductance K+ (SK)-mediated hyperpolarization and a decrease of transient receptor potential C (TRPC)-mediated sustained depolarization. Consistent with a role for DISC1 in regulation of CAMP signaling, forskolin-induced CAMP production also increased intracellular Ca2+ waves, I-SK and decreased I-TRPC. Lastly, inhibiting CAMP generation with guanfacine, an ?2A-noradrenergic agonist, normalized the function of SK and TRPC channels. Based on our findings, we propose that diminished DISC1 function, such as occurs in some mental disorders, can lead to the disruption of normal patterns of prefrontal cortex activity through the loss of CAMP regulation of metabotropic glutamate receptor-mediated intracellular Ca2+ waves, SK and TRPC channel activity. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 183 | FEBS J. 2014 Nov 281: 4792-804 |
| PMID | 25154512 |
| Title | Agonist-dependent and -independent dopamine-1-like receptor signalling differentially regulates downstream effectors. |
| Abstract | De-regulation of energy metabolism by the dopaminergic system is linked to neurological diseases such as schizophrenia and bipolar disorder. Inverse agonists are thought to be more beneficial in treating neurological diseases than neutral antagonists, but only limited experimental data are available regarding the impact of constitutive signalling on energy metabolism. The aim of the present study was to assess the impact of constitutive dopamine-1 receptor (D1R) and dopamine-5 receptor (D5R) signalling on downstream targets in transiently and stably transfected HEK293T cells. The high constitutive activity of D5R was accompanied by increased Na(+)/H(+) exchanger (NHE) activity and accelerated glucose degradation due to increased transcription and translation of the Na, K-ATPase-?3 and NHE-2. Chronic treatment with an agonist increased the mRNA levels of the ?2 Na,K-ATPase, NHE-2 and NHE-3. Constitutive D5R activation of a CAMP response element-based reporter was regulated by G protein-coupled receptor kinase 2, but this did not affect the cell-surface abundance of the receptor. Our data suggest that constitutive and agonist-induced activity of D5R differentially regulates the activity and expression of proteins. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 184 | J. Nerv. Ment. Dis. 2014 Mar 202: 181-5 |
| PMID | 24566502 |
| Title | Psychiatry on trial: the Norway 2011 massacre. |
| Abstract | On July 22, 2011, Anders Breivik, a Norwegian citizen, detonated a fertilizer bomb near government buildings in Oslo, killing eight people, and then proceeded to a nearby island where the Labor Party was holding a youth CAMP. There, he killed 69 people before being arrested. Just before these events, he posted a "compendium" on the Web explaining his actions and encouraging others to do likewise. Much of the ensuing media coverage and trial focused on whether he was sane and whether he had a psychiatric diagnosis. One team of court-appointed psychiatrists found him to be psychotic with a diagnosis of paranoid schizophrenia and legally insane. A second team found him neither psychotic nor schizophrenic and, thus, legally sane. Their contrary opinions were not reconciled by observing his behavior in court. We discuss why experienced psychiatrists reached such fundamentally opposing diagnostic conclusions about a "home-grown" terrorist holding extreme political views. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 185 | J Affect Disord 2014 Jan 152-154: 326-33 |
| PMID | 24148789 |
| Title | Alteration of cyclic-AMP response element binding protein in the postmortem brain of subjects with bipolar disorder and schizophrenia. |
| Abstract | Abnormalities of cyclic-AMP (CAMP) response element binding protein (CREB) function has been suggested in bipolar (BP) illness and schizophrenia (SZ), based on both indirect and direct evidence. To further elucidate the role of CREB in these disorders, we studied CREB expression and function in two brain areas implicated in these disorders, i.e., dorsolateral prefrontal cortex (DLPFC) and cingulate gyrus (CG). We determined CREB protein expression using Western blot technique, CRE-DNA binding using gel shift assay, and mRNA expression using real-time RT-polymerase chain reaction (qPCR) in DLPFC and CG of the postmortem brain of BP (n=19), SZ (n=20), and normal control (NC, n=20) subjects. We observed that CREB protein and mRNA expression and CRE-DNA binding activity were significantly decreased in the nuclear fraction of DLPFC and CG obtained from BP subjects compared with NC subjects. However, the protein and mRNA expression and CRE-DNA binding in SZ subjects was significantly decreased in CG, but not in DLPFC, compared with NC. These studies thus indicate region-specific abnormalities of CREB expression and function in both BP and SZ. They suggest that abnormalities of CREB in CG may be associated with both BP and SZ, but its abnormality in DLPFC is specific to BP illness. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 186 | Cent Nerv Syst Agents Med Chem 2014 -1 14: 72-82 |
| PMID | 25540976 |
| Title | Regulation of dopamine signaling in the striatum by phosphodiesterase inhibitors: novel therapeutics to treat neurological and psychiatric disorders. |
| Abstract | Abnormal dopamine neurotransmission has been linked to a wide array of motor, cognitive, and psychiatric disorders. Dopamine binds and regulates intracellular signals through D1-like (D1 and D5) and D2-like (D2, D3, and D4) G-protein coupled receptors. Activation of D1- like receptors stimulates CAMP/PKA signaling via Gs mediated activation of adenylyl cyclase. In contrast, activation of D2-like receptors inhibits CAMP/PKA signaling by Gi inhibition of adenylyl cyclase. In the brain, dopamine signaling is tightly regulated by cyclic nucleotide phosphodiesterases (PDEs). PDEs are a family of enzymes that selectively degrade CAMP and cGMP. There are 11 different families of PDEs that vary in their substrate specificity, kinetic properties, mode of regulation, intracellular localization, and tissue expression patterns. A number of PDE families are highly expressed in the striatum including PDE1, PDE2, PDE4, and PDE10. There is a growing amount of evidence to suggest that these enzymes play a critical role in modulating dopamine signaling and selective inhibitors of these enzymes are currently being explored as novel therapeutics to treat schizophrenia, Huntington's disease, cognitive disorders and Parkinson's disease. The aim of this review is to summarize the distinct roles of different PDEs in regulating dopamine signaling in the striatum. In addition, we will briefly review the therapeutic potential of selective PDE inhibitors to treat neurological and psychiatric disorders associated with abnormal striatal function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 187 | J. Nerv. Ment. Dis. 2014 Mar 202: 181-5 |
| PMID | 24566502 |
| Title | Psychiatry on trial: the Norway 2011 massacre. |
| Abstract | On July 22, 2011, Anders Breivik, a Norwegian citizen, detonated a fertilizer bomb near government buildings in Oslo, killing eight people, and then proceeded to a nearby island where the Labor Party was holding a youth CAMP. There, he killed 69 people before being arrested. Just before these events, he posted a "compendium" on the Web explaining his actions and encouraging others to do likewise. Much of the ensuing media coverage and trial focused on whether he was sane and whether he had a psychiatric diagnosis. One team of court-appointed psychiatrists found him to be psychotic with a diagnosis of paranoid schizophrenia and legally insane. A second team found him neither psychotic nor schizophrenic and, thus, legally sane. Their contrary opinions were not reconciled by observing his behavior in court. We discuss why experienced psychiatrists reached such fundamentally opposing diagnostic conclusions about a "home-grown" terrorist holding extreme political views. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 188 | ACS Chem. Biol. 2014 Dec 9: 2823-32 |
| PMID | 25295858 |
| Title | Chemoproteomics demonstrates target engagement and exquisite selectivity of the clinical phosphodiesterase 10A inhibitor MP-10 in its native environment. |
| Abstract | Phosphodiesterases (PDEs) regulate the levels of the second messengers CAMP and cGMP and are important drug targets. PDE10A is highly enriched in medium spiny neurons of the striatum and is an attractive drug target for the treatment of basal ganglia diseases like schizophrenia, Parkinson's disease, or Huntington's disease. Here we describe the design, synthesis, and application of a variety of chemical biology probes, based on the first clinically tested PDE10A inhibitor MP-10, which were used to characterize the chemoproteomic profile of the clinical candidate in its native environment. A clickable photoaffinity probe was used to measure target engagement of MP-10 and revealed differences between whole cell and membrane preparations. Moreover, our results illustrate the importance of the linker design in the creation of functional probes. Biotinylated affinity probes allowed identification of drug-interaction partners in rodent and human tissue and quantitative mass spectrometry analysis revealed highly specific binding of MP-10 to PDE10A with virtually no off-target binding. The profiling of PDE10A chemical biology probes described herein illustrates a strategy by which high affinity inhibitors can be converted into probes for determining selectivity and target engagement of drug candidates in complex biological matrices from native sources. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 189 | Eur Neuropsychopharmacol 2014 Oct 24: 1698-708 |
| PMID | 25108314 |
| Title | ASP5736, a novel 5-HT5A receptor antagonist, ameliorates positive symptoms and cognitive impairment in animal models of schizophrenia. |
| Abstract | We recently identified ASP5736, (N-(diaminomethylene)-1-(3,5-difluoropyridin-4-yl)-4-fluoroisoquinoline-7-carboxamide (2E)-but-2-enedioate), a novel antagonist of 5-HT5A receptor, and here describe the in vitro and in vivo characterization of this compound. ASP5736 exhibited a high affinity for the human 5-HT5A receptor (Ki = 3.6 ± 0.66 nM) and antagonized 5-carboxamidotryptamine (5-CT)-induced Ca(2+) influx in human cells stably expressing the 5-HT5A receptor with approximately 200-fold selectivity over other receptors, including other 5-HT receptor subtypes, enzymes, and channels except human 5-HT2c receptor (Ki = 286.8 nM) and 5-HT7 receptor (Ki = 122.9 nM). Further, ASP5736 dose-dependently antagonized the 5-CT-induced decrease in CAMP levels in HEK293 cells stably expressing the 5-HT5A receptor. We then evaluated the effects of ASP5736 on cognitive impairments in several animal models of schizophrenia. Working memory deficit in MK-801-treated mice and visual learning deficit in neonatally phencyclidine (PCP)-treated mice were both ameliorated by ASP5736. In addition, ASP5736 also attenuated MK-801- and methamphetamine (MAP)-induced hyperactivity in mice without causing sedation, catalepsy, or plasma prolactin increase. The addition of olanzapine did not affect ASP5736-induced cognitive enhancement, and neither the sedative nor cataleptogenic effects of olanzapine were worsened by ASP5736. These results collectively suggest that ASP5736 is a novel and potent 5-HT5A receptor antagonist that not only ameliorates positive-like symptoms but also cognitive impairments in animal models of schizophrenia, without adverse effects. Present studies also indicate that ASP5736 holds potential to satisfy currently unmet medical needs for the treatment of schizophrenia by either mono-therapy or co-administered with commercially available antipsychotics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 190 | J Psychiatr Res 2014 Oct 57: 84-9 |
| PMID | 25043418 |
| Title | Molecular evolution in the CREB1 signal pathway and a rare haplotype in CREB1 with genetic predisposition to schizophrenia. |
| Abstract | CREB1 is a CAMP responsive transcriptional factor which plays a key role in neural development. CREB1 signal pathway (CSP) has been implicated repeatedly in studies of predisposition for schizophrenia. We speculated that CSP has undergone positive selection during evolution of modern human and some genes that have undergone natural selection in the past may predispose to schizophrenia (SCZ) in modern time. Positive selection and association analysis were employed to explore the molecular evolution of CSP and association with schizophrenia. Our results showed a pan-ethnic selection event on NRG1 and CREB1, as confirmed in all 14 ethnic populations studied, which also suggested a selection process occurred before the "Out of Africa" scenario. Analysis of 62 SNPs covering 6 CSP genes in 2019 Han Chinese (976 SCZ patients and 1043 healthy individuals) showed an association of two SNPs (rs4379857, P = 0.009, OR [95% CI]: 1.200 [1.379-1.046]; rs2238751, P = 0.023, OR [95% CI]: 1.253 [1.522-1.032]) with SCZ. However, none of these significances survived after multiple testing corrections. Nonetheless, we observed an association of a rare CREB1 haplotype CCGGC (Bonferroni corrected P = 1.74 × 10(-5)) with SCZ. Our study showed that there was substantial population heterogeneity in genetic predisposition to SCZ, and different genes in the CSP pathway may predispose to SCZ in different populations. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 191 | Stem Cells 2014 Sep 32: 2454-66 |
| PMID | 24806094 |
| Title | Gastrin-releasing peptide contributes to the regulation of adult hippocampal neurogenesis and neuronal development. |
| Abstract | In the postnatal hippoCAMPus, newly generated neurons contribute to learning and memory. Disruptions in neurogenesis and neuronal development have been linked to cognitive impairment and are implicated in a broad variety of neurological and psychiatric disorders. To identify putative factors involved in this process, we examined hippoCAMPal gene expression alterations in mice possessing a heterozygous knockout of the calcium/calmodulin-dependent protein kinase II alpha heterozygous knockout gene (CaMK2?-hKO), an established model of cognitive impairment that also displays altered neurogenesis and neuronal development. Using this approach, we identified gastrin-releasing peptide (GRP) as the most dysregulated gene. In wild-type mice, GRP labels NeuN-positive neurons, the lone exception being GRP-positive, NeuN-negative cells in the subgranular zone, suggesting GRP expression may be relevant to neurogenesis and/or neuronal development. Using a model of in vitro hippoCAMPal neurogenesis, we determined that GRP signaling is essential for the continued survival and development of newborn neurons, both of which are blocked by transient knockdown of GRP's cognate receptor (GRPR). Furthermore, GRP appears to negatively regulate neurogenesis-associated proliferation in neural stem cells both in vitro and in vivo. Intracerebroventricular infusion of GRP resulted in a decrease in immature neuronal markers, increased CAMP response element-binding protein (CREB) phosphorylation, and decreased neurogenesis. Despite increased levels of GRP mRNA, CaMK2?-hKO mutant mice expressed reduced levels of GRP peptide. This lack of GRP may contribute to the elevated neurogenesis and impaired neuronal development, which are reversed following exogenous GRP infusion. Based on these findings, we hypothesize that GRP modulates neurogenesis and neuronal development and may contribute to hippoCAMPus-associated cognitive impairment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 192 | Hum Psychopharmacol 2014 Jul 29: 330-5 |
| PMID | 24737441 |
| Title | Protein kinase cAMP-dependent regulatory type II beta (PRKAR2B) gene variants in antipsychotic-induced weight gain. |
| Abstract | Antipsychotics are effective in treating schizophrenia symptoms. However, the use of clozapine and olanzapine in particular are associated with significant weight gain. Mouse and human studies suggest that the protein kinase CAMP-dependent regulatory type II beta (PRKAR2B) gene may be involved in energy metabolism, and there is evidence that it is associated with clozapine's effects on triglyceride levels. We aimed at assessing PRKAR2B's role in antipsychotic-induced weight gain in schizophrenia patients. DNA samples from adult schizophrenia or schizoaffective disorder patients of mixed ancestry were genotyped, and weight gain was assessed. We analyzed 16 tag single-nucleotide polymorphisms across the PRKAR2B gene in a Caucasian subset treated either with clozapine or olanzapine (N?=?99). Linear regression based on an additive model was performed with the inclusion of relevant covariates. Normalized per cent weight change was analyzed, revealing that patients with the minor allele at rs9656135 had a mean weight increase of 4.1%, whereas patients without this allele had an increase of 3.4%. This association is not significant after correcting for multiple testing. Because of limited power, PRKAR2B's role in antipsychotic-induced weight gain is unclear, but biological evidence suggests that PRKAR2B may be involved. Further research in larger sample sizes is warranted. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 193 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2014 Aug 53: 123-8 |
| PMID | 24704945 |
| Title | Elevated postmortem striatal t-DARPP expression in schizophrenia and associations with DRD2/ANKK1 polymorphism. |
| Abstract | Dopamine- and CAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) and calcineurin (CaN) have been implicated in the pathogenesis of schizophrenia because they function as molecular integrators of dopamine and glutamate signaling. DARPP-32 and CaN are mainly expressed in the caudate nucleus and putamen; however, a few postmortem brain studies have focused on DARPP-32 expression in striatum from patients with schizophrenia. We used immunoblotting techniques and postmortem tissue samples from patients with schizophrenia and from normal control individuals to examine the expression of two major DARPP-32 isoforms, full-length (FL-DARPP) and truncated (t-DARPP), and of CaN in the striatum. We also assessed whether there was any significant correlation between the expression levels of either protein and the A1 allele of Taq1A genotype in the dopamine D2 receptor (DRD2) gene/ankyrin-repeat containing kinase 1 (ANKK1) gene. We found that the mean t-DARPP expression level in the caudate was higher in patients with schizophrenia than in control individuals (P<0.05) and the A1 allele of Taq1A genotype in DRD2/ANKK1 was significantly associated with elevated expression of t-DARPP in the caudate. Also, the A1 allele was significantly correlated with the total score of antemortem psychiatric symptoms. These results may reflect potential molecular mechanisms important to the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 194 | Behav. Brain Res. 2014 Jul 268: 48-54 |
| PMID | 24698799 |
| Title | Genetic deletion of PDE10A selectively impairs incentive salience attribution and decreases medium spiny neuron excitability. |
| Abstract | The striatum is the main input structure to the basal ganglia and consists mainly out of medium spiny neurons. The numerous spines on their dendrites render them capable of integrating cortical glutamatergic inputs with a motivational dopaminergic signal that originates in the midbrain. This integrative function is thought to underly attribution of incentive salience, a process that is severely disrupted in schizophrenic patients. Phosphodiesterase 10A (PDE10A) is located mainly to the striatal medium spiny neurons and hydrolyses CAMP and cGMP, key determinants of MSN signaling. We show here that genetic depletion of PDE10A critically mediates attribution of salience to reward-predicting cues, evident in impaired performance in PDE10A knockout mice in an instrumentally conditioned reinforcement task. We furthermore report modest impairment of latent inhibition in PDE10A knockout mice, and unaltered prepulse inhibition. We suggest that the lack of effect on PPI is due to the pre-attentional nature of this task. Finally, we performed whole-cell patch clamp recordings and confirm suggested changes in intrinsic membrane excitability. A decrease in spontaneous firing in striatal medium spiny neurons was found. These data show that PDE10A plays a pivotal role in striatal signaling and striatum-mediated salience attribution. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 195 | Prog Mol Biol Transl Sci 2014 -1 122: 211-31 |
| PMID | 24484703 |
| Title | Molecular influences on working memory circuits in dorsolateral prefrontal cortex. |
| Abstract | The working memory circuits of the primate dorsolateral prefrontal cortex (dlPFC) are modulated in a unique manner, often opposite to the molecular mechanisms needed for long-term memory consolidation. Working memory, our "mental sketch pad" is an ephemeral process, whereby transient, mental representations form the foundation for abstract thought. The microcircuits that generate mental representations are found in deep layer III of the dlPFC, where pyramidal cells excite each other to keep information "in mind" through NMDA receptor synapses on spines. The catecholaminergic and cholinergic arousal systems have rapid and flexible influences on the strength of these connections, thus allowing coordination between arousal and cognitive states. These modulators can rapidly weaken connectivity, for example, as occurs during uncontrollable stress, via feedforward calcium-CAMP signaling opening potassium (K(+)) channels near synapses on spines. Lower levels of calcium-CAMP-K(+) channel signaling provide negative feedback within recurrent excitatory circuits, and help to gate inputs to shape the contents of working memory. There are also explicit mechanisms to inhibit calcium-CAMP signaling and strengthen connectivity, for example, postsynaptic ?2A-adrenoceptors on spines. This work has led to the development of the ?2A agonist, guanfacine, for the treatment of a variety of dlPFC disorders. In mental illness, there are a variety of genetic insults to the molecules that normally serve to inhibit calcium-CAMP signaling in spines, thus explaining why so many genetic insults can lead to the same phenotype of impaired dlPFC cognitive function. Thus, the molecular mechanisms that provide mental flexibility may also confer vulnerability when dysregulated in cognitive disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 196 | Neuropharmacology 2014 Apr 79: 559-66 |
| PMID | 24440754 |
| Title | Haloperidol-induced Nur77 expression in striatopallidal neurons is under the control of protein phosphatase 1 regulation by DARPP-32. |
| Abstract | Impaired dopaminergic signaling in the striatum is involved in diseases as diverse as Parkinson's disease, addiction, and schizophrenia. An important pathophysiological aspect is the loss of balance between striatopallidal and striatonigral pathways. Nur77 is an orphan nuclear receptor and dopamine-regulated immediate-early gene. Classical antipsychotic drugs widely used in the treatment of schizophrenia, such as haloperidol, increase Nur77 mRNA expression in the striatum. However, little is known about the intracellular signaling pathways involved in Nur77 induction. Here, using pharmacological approaches and transgenic mutant mice, we investigated the mechanisms underlying the up-regulation of Nur77 protein expression in the dorsal striatum after haloperidol injection. In drd1a::EGFP transgenic mice that express GFP in D1 neurons, Nur77 up-regulation induced by haloperidol occurred predominantly in GFP-negative neurons. In G?olf heterozygous mutant mice, in which CAMP production in response to A2A stimulation is impaired in the striatum, haloperidol effect was not altered. In contrast, in DARPP-32 knock-in mutant mice bearing a T34A point mutation of the site responsible for CAMP-dependent phosphatase 1 inhibition, Nur77 up-regulation by haloperidol was prevented. Haloperidol also induced Nur77 protein in D2 neurons of the nucleus accumbens core of wild type but not T34A knock-in mice. Thus, our results show that expression of Nur77 is induced by haloperidol in D2 receptors-expressing medium-sized spiny neurons, through CAMP-dependent regulation of protein phosphatase 1, which is likely to modulate the effects of other protein kinases. Our results clarify the mechanisms of Nur77 induction by antipsychotic and its possible contribution to extrapyramidal effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 197 | Mol. Psychiatry 2014 Feb 19: 192-9 |
| PMID | 23295814 |
| Title | Revisiting DARPP-32 in postmortem human brain: changes in schizophrenia and bipolar disorder and genetic associations with t-DARPP-32 expression. |
| Abstract | Dopamine- and CAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32 or PPP1R1B) has been of interest in schizophrenia owing to its critical function in integrating dopaminergic and glutaminergic signaling. In a previous study, we identified single-nucleotide polymorphisms (SNPs) and a frequent haplotype associated with cognitive and imaging phenotypes that have been linked with schizophrenia, as well as with expression of prefrontal cortical DARPP-32 messenger RNA (mRNA) in a relatively small sample of postmortem brains. In this study, we examined the association of expression of two major DARPP-32 transcripts, full-length (FL-DARPP-32) and truncated (t-DARPP-32), with genetic variants of DARPP-32 in three brain regions receiving dopaminergic input and implicated in schizophrenia (the dorsolateral prefrontal cortex (DLPFC), hippoCAMPus and caudate) in a much larger set of postmortem samples from patients with schizophrenia, bipolar disorder, major depression and normal controls (>700 subjects). We found that the expression of t-DARPP-32 was increased in the DLPFC of patients with schizophrenia and bipolar disorder, and was strongly associated with genotypes at SNPs (rs879606, rs90974 and rs3764352), as well as the previously identified 7-SNP haplotype related to cognitive functioning. The genetic variants that predicted worse cognitive performance were associated with higher t-DARPP-32 expression. Our results suggest that variation in PPP1R1B affects the abundance of the splice variant t-DARPP-32 mRNA and may reflect potential molecular mechanisms implicated in schizophrenia and affective disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 198 | Behav. Brain Res. 2014 Jul 268: 48-54 |
| PMID | 24698799 |
| Title | Genetic deletion of PDE10A selectively impairs incentive salience attribution and decreases medium spiny neuron excitability. |
| Abstract | The striatum is the main input structure to the basal ganglia and consists mainly out of medium spiny neurons. The numerous spines on their dendrites render them capable of integrating cortical glutamatergic inputs with a motivational dopaminergic signal that originates in the midbrain. This integrative function is thought to underly attribution of incentive salience, a process that is severely disrupted in schizophrenic patients. Phosphodiesterase 10A (PDE10A) is located mainly to the striatal medium spiny neurons and hydrolyses CAMP and cGMP, key determinants of MSN signaling. We show here that genetic depletion of PDE10A critically mediates attribution of salience to reward-predicting cues, evident in impaired performance in PDE10A knockout mice in an instrumentally conditioned reinforcement task. We furthermore report modest impairment of latent inhibition in PDE10A knockout mice, and unaltered prepulse inhibition. We suggest that the lack of effect on PPI is due to the pre-attentional nature of this task. Finally, we performed whole-cell patch clamp recordings and confirm suggested changes in intrinsic membrane excitability. A decrease in spontaneous firing in striatal medium spiny neurons was found. These data show that PDE10A plays a pivotal role in striatal signaling and striatum-mediated salience attribution. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 199 | Mol Med Rep 2015 Apr 11: 2927-34 |
| PMID | 25503442 |
| Title | WSKY, a traditional Chinese decoction, rescues cognitive impairment associated with NMDA receptor antagonism by enhancing BDNF/ERK/CREB signaling. |
| Abstract | Warm?supplementing kidney yang (WSKY) is an herbal prescription that has been used in Traditional Chinese Medicine for the treatment of psychiatric conditions. A previous study by our group found that WSKY significantly improved cognitive function of schizophrenia patients. In the present study, the effects of WSKY on cognitive function and their underlying mechanisms were investigated. WSKY was administered to an MK?801?induced rat model of chronic schizophrenia for 14 days. Memory performance was assessed using the Morris water maze (MWM) test. The expression of brain?derived neurotrophic factor (BDNF), activation of CAMP response element binding protein (pCREB/CREB) and activation of extracellular signal?regulated kinase (pERK/ERK) in the hippoCAMPus was detected using western blot analysis. In the acquisition phase of the MWM test, the escape latency was significantly increased in the MK?801?treated group compared with the normal control group (P<0.01). Treatment with WSKY for 14 days at doses of 100 or 250 mg/kg rescued this cognitive impairment (P<0.05). In the probe test, 250 mg/kg WSKY treatment increased the time spent in the target quadrant (P<0.05) and number of platform crossings (P<0.01). Western blot analysis demonstrated that the levels of BDNF expression in the hippoCAMPus of rats without behavioral tests were elevated following 14 days of WSKY treatment, and the effect of WSKY treatment on hippoCAMPal BDNF expression was presented in an inverted U?shaped dose?response pattern. The pERK1/2 in the hippoCAMPus was significantly enhanced following 100 mg/kg (P<0.01) and 250 mg/kg (P<0.01) WSKY treatment, while only 250 mg/kg WSKY increased the phosphorylation of CREB (P<0.01). The results of the present study indicated that WSKY enhances cognitive performance via the upregulation of BDNF/ERK/CREB signaling, and that WSKY has potential therapeutic implications for cognitive impairment of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 200 | J. Neurochem. 2015 Nov 135: 598-605 |
| PMID | 26212236 |
| Title | DISC1 regulates expression of the neurotrophin VGF through the PI3K/AKT/CREB pathway. |
| Abstract | Disrupted in schizophrenia (DISC1) is a risk factor for chronic mental disease. In a previous proteomic study, we reported that knocking down DISC1 results in a sharp decrease in the levels of the neuropeptide precursor VGF (non-acronymic) and leads to reduced activation of CAMP response element-binding protein (CREB) and protein kinase B (AKT) in neurons. The main objective of this study is to complete the characterization of the route, or routes, involving AKT and CREB through which DISC1 modulates the expression of VGF. For that we explored known players upstream of AKT and the DISC1 binding partners glycogen synthase kinase-3 beta and Phosphodiesterase-4, which might in turn reach out to CREB in murine neuron primary culture. We found that DISC1 modulates the activation of Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K). Furthermore, pharmacological inhibition of PI3K resulted in decreased expression of VGF. All this suggests that the PI3K/AKT pathway plays a role in mediating the effects of DISC1 silencing on VGF expression. Given the important roles of VGF in mental disease, and its drugability, the DISC1-VGF connection might prove to be important for efforts to develop new therapies for these diseases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 201 | Synapse 2015 Oct 69: 484-96 |
| PMID | 26178667 |
| Title | Inhibition of PDE2A, but not PDE9A, modulates presynaptic short-term plasticity measured by paired-pulse facilitation in the CA1 region of the hippocampus. |
| Abstract | Phosphodiesterase (PDE) inhibitors are currently considered promising therapeutic targets for treatment of cognitive impairment in diseases such as schizophrenia and Alzheimer's disease. Inhibitors of PDE2A and PDE9A have emerged as potential candidates shown to improve synaptic plasticity and memory function in animals. However, the functional relevance of their putative different localization in the neuron is not understood. Thus, this study aims at elucidating potential presynaptic effects of PDE2A inhibition in comparison to the inhibition of PDE9A. For this purpose, we used paired-pulse facilitation (PPF), a model of short-term synaptic plasticity related to presynaptic function. First, we performed a series of experiments to validate the model in acute rat hippoCAMPal slices using several reference substances including calcium channel blockers, glutamatergic receptor antagonists, and GPCR agonists. Second, we analysed the effect of PDE2A and PDE9A inhibition and their role regulating the influence that the second messengers CAMP and cGMP exert on basal transmission. Our results show that the interplay between the adenylyl cyclase activator forskolin, the soluble guanylyl cyclase activator BAY 41-8543 and the PDE2A inhibitor PF-999 reveals a primarily presynaptic mechanism of action of PDE2A inhibition. On the contrary, inhibition of PDE9A did not alter PPF under similar conditions. In conclusion, these data provide new evidence supporting a role of PDE2A modulating short-term synaptic plasticity. Moreover, this function of PDE2A is suggested to rely on an active modulation of the CAMP hydrolysis as a response to changes in cGMP levels at the presynaptic level. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 202 | Br. J. Pharmacol. 2015 Jan 172: 1-23 |
| PMID | 25671228 |
| Title | Dopamine receptors - IUPHAR Review 13. |
| Abstract | The variety of physiological functions controlled by dopamine in the brain and periphery is mediated by the D1, D2, D3, D4 and D5 dopamine GPCRs. Drugs acting on dopamine receptors are significant tools for the management of several neuropsychiatric disorders including schizophrenia, bipolar disorder, depression and Parkinson's disease. Recent investigations of dopamine receptor signalling have shown that dopamine receptors, apart from their canonical action on CAMP-mediated signalling, can regulate a myriad of cellular responses to fine-tune the expression of dopamine-associated behaviours and functions. Such signalling mechanisms may involve alternate G protein coupling or non-G protein mechanisms involving ion channels, receptor tyrosine kinases or proteins such as ?-arrestins that are classically involved in GPCR desensitization. Another level of complexity is the growing appreciation of the physiological roles played by dopamine receptor heteromers. Applications of new in vivo techniques have significantly furthered the understanding of the physiological functions played by dopamine receptors. Here we provide an update of the current knowledge regarding the complex biology, signalling, physiology and pharmacology of dopamine receptors. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 203 | Mol. Neurobiol. 2015 Sep -1: -1 |
| PMID | 26328537 |
| Title | Pathophysiological Roles of Cyclooxygenases and Prostaglandins in the Central Nervous System. |
| Abstract | Cyclooxygenases (COXs) oxidize arachidonic acid to prostaglandin (PG) G2 and H2 followed by PG synthases that generates PGs and thromboxane (TX) A2. COXs are divided into COX-1 and COX-2. In the central nervous system, COX-1 is constitutively expressed in neurons, astrocytes, and microglial cells. COX-2 is upregulated in these cells under pathophysiological conditions. In hippoCAMPal long-term potentiation, COX-2, PGE synthase, and PGE2 are induced in post-synaptic neurons. PGE2 acts pre-synaptic EP2 receptor, generates CAMP, stimulates protein kinase A, modulates voltage-dependent calcium channel, facilitates glutamatergic synaptic transmission, and potentiates long-term plasticity. PGD2, PGE2, and PGI2 exhibit neuroprotective effects via Gs-coupled DP1, EP2/EP4, and IP receptors, respectively. COX-2, PGD2, PGE2, PGF2?, and TXA2 are elevated in stroke. COX-2 inhibitors exhibit neuroprotective effects in vivo and in vitro models of stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy, and schizophrenia, suggesting neurotoxicities of COX products. PGE2, PGF2?, and TXA2 can contribute to the neurodegeneration via EP1, FP, and TP receptors, respectively, which are coupled with Gq, stimulate phospholipase C and cleave phosphatidylinositol diphosphate to produce inositol triphosphate and diacylglycerol. Inositol triphosphate binds to inositol triphosphate receptor in endoplasmic reticulum, releases calcium, and results in increasing intracellular calcium concentrations. Diacylglycerol activates calcium-dependent protein kinases. PGE2 disrupts Ca(2+) homeostasis by impairing Na(+)-Ca(2+) exchange via EP1, resulting in the excess Ca(2+) accumulation. Neither PGE2, PGF2?, nor TXA2 causes neuronal cell death by itself, suggesting that they might enhance the ischemia-induced neurodegeneration. Alternatively, PGE2 is non-enzymatically dehydrated to a cyclopentenone PGA2, which induces neuronal cell death. Although PGD2 induces neuronal apoptosis after a lag time, neither DP1 nor DP2 is involved in the neurotoxicity. As well as PGE2, PGD2 is non-enzymatically dehydrated to a cyclopentenone 15-deoxy-?(12,14)-PGJ2, which induces neuronal apoptosis without a lag time. However, neurotoxicities of these cyclopentenones are independent of their receptors. The COX-2 inhibitor inhibits both the anchorage-dependent and anchorage-independent growth of glioma cell lines regardless of COX-2 expression, suggesting that some COX-2-independent mechanisms underlie the antineoplastic effect of the inhibitor. PGE2 attenuates this antineoplastic effect, suggesting that the predominant mechanism is COX-dependent. COX-2 or EP1 inhibitors show anti-neoplastic effects. Thus, our review presents evidences for pathophysiological roles of cyclooxygenases and prostaglandins in the central nervous system. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 204 | J. Neurochem. 2015 Mar 132: 677-86 |
| PMID | 25639954 |
| Title | Protein kinase A directly phosphorylates metabotropic glutamate receptor 5 to modulate its function. |
| Abstract | Metabotropic glutamate receptor 5 (mGluR5) regulates excitatory post-synaptic signaling in the central nervous system (CNS) and is implicated in various CNS disorders. Protein kinase A (PKA) signaling is known to play a critical role in neuropsychiatric disorders such as Parkinson's disease, schizophrenia, and addiction. Dopamine signaling is known to modulate the properties of mGluR5 in a CAMP- and PKA-dependent manner, suggesting that mGluR5 may be a direct target for PKA. Our study identifies mGluR5 at Ser870 as a direct substrate for PKA phosphorylation and demonstrates that this phosphorylation plays a critical role in the PKA-mediated modulation of mGluR5 functions such as extracellular signal-regulated kinase phosphorylation and intracellular Ca(2+) oscillations. The identification of the molecular mechanism by which PKA signaling modulates mGluR5-mediated cellular responses contributes to the understanding of the interaction between dopaminergic and glutamatergic neuronal signaling. We identified serine residue 870 (S870) in metabotropic glutamate receptor 5 (mGluR5) as a direct substrate for protein kinase A (PKA). The phosphorylation of this site regulates the ability of mGluR5 to induce extracellular signal-regulated kinase (ERK) phosphorylation and intracellular Ca(2+) oscillations. This study provides a direct molecular mechanism by which PKA signaling interacts with glutamate neurotransmission. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 205 | Curr. Pharm. Des. 2015 -1 21: 378-88 |
| PMID | 25159072 |
| Title | Emerging biology of PDE10A. |
| Abstract | Cyclic AMP and cyclic GMP are essential second messengers that regulate multiple signaling pathways in virtually all cell types. Their accumulation in cells is finely regulated by cyclic nucleotide phosphodiesterases (PDEs), the only enzymes that can degrade these signaling molecules and thus provide exquisite control over intracellular signaling processes. One PDE family, PDE10A, is highly enriched in the brain and its unique expression profile in specific brain regions of interest, in particular to antipsychotic treatment, has made it an attractive therapeutic target for the treatment of schizophrenia. However, after a Phase II trial failure of a selective PDE10A inhibitor for the treatment of schizophrenia, it has encouraged the field to reexamine the role of this enzyme in the brain, and the possible CNS disorders in which PDE10A inhibition could be therapeutic. We will review the localization of PDE10A, both within the brain and the neuron and discuss how its role in regulating CAMP and cGMP accumulation modulates intracellular signaling pathways. Since this cellular signaling has best been documented in the striatum, we will focus our discussion of PDE10A in the context of disorders that affect the basal ganglia, including psychiatric disorders such as bipolar disorder and autism spectrum disorders and the movement disorders, including Parkinson's disease and Huntington's disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 206 | Int. J. Neuropsychopharmacol. 2015 Dec -1: -1 |
| PMID | 26657176 |
| Title | Involvement of the Striatal Medium Spiny Neurons of the Direct Pathway in the Motor Stimulant Effects of Phencyclidine. |
| Abstract | The psychotomimetic phencyclidine (PCP) produces behavioral symptoms similar to those observed in schizophrenia, accompanied by increased motor activity. The dopamine and adenosine 3',5'-cyclic monophosphate-regulated phosphoprotein of 32kDa (DARPP-32) is enriched in the medium spiny neurons (MSNs) of the striatum and has been implicated in the actions of PCP. We examined the effects of deletion of DARPP-32 in distinct populations of striatal MSNs, on the ability of PCP to induce motor activation and memory deficit. The effects of PCP were examined in mice with conditional knockout of DARPP-32 in the MSNs of the direct, or indirect pathway. DARPP-32 phosphorylation was determined by Western blotting. The motor stimulant effects of PCP were determined by measuring locomotion following acute and chronic administration. Memory deficit was evaluated using the passive avoidance test. Loss of DARPP-32 in direct MSNs prevents PCP-induced phosphorylation and abolishes the motor stimulation effects of PCP. In contrast, lack of DARPP-32 in indirect MSNs does not affect the ability of PCP to promote DARPP-32 phosphorylation and to increase motor activity. The impairment in passive avoidance induced by PCP is independent of the expression of DARPP-32 in direct or indirect MSNs. The increase in DARPP-32 phosphorylation induced by PCP occurs selectively in the MSNs of the direct pathway, which are also specifically involved in the motor stimulant effects of this drug. The memory deficit induced by PCP is not linked to the expression of DARPP-32 in striatal MSNs. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 207 | J. Neurochem. 2015 Nov -1: -1 |
| PMID | 26560964 |
| Title | Severe learning deficits of IRSp53 mutant mice are caused by altered NMDA receptor dependent signal transduction. |
| Abstract | Learning and memory is dependent on postsynaptic architecture and signaling processes in forebrain regions. The insulin receptor substrate protein of 53 kDa (IRSp53, also known as Baiap2) is a signaling and adapter protein in forebrain excitatory synapses. Mice deficient in IRSp53 display enhanced levels of postsynaptic N-methyl-D-aspartate receptors (NMDARs) and long-term potentiation (LTP) associated with severe learning deficits. In humans, reduced IRSp53/Baiap2 expression is associated with a variety of neurological disorders including autism, schizophrenia and Alzheimer's disease. Here we analyzed mice lacking one copy of the gene coding for IRSp53 using behavioural tests including contextual fear conditioning and the puzzle box. We show that a 50% reduction in IRSp53 levels strongly affects the performance in fear-evoking learning paradigms. This correlates with increased targeting of NMDARs to the postsynaptic density (PSD) in hippoCAMPi of both heterozygous and knock out (ko) mice at the expense of extrasynaptic NMDARs. As hippoCAMPal NMDAR dependent LTP is enhanced in IRSp53-deficient mice, we investigated signaling cascades important for the formation of fear evoked memories. Here we observed a dramatic increase in CAMP response element-binding protein (CREB) dependent signaling in heterozygous and IRSp53 deficient mice, necessary for the transcriptional dependent phase of LTP. In contrast, activation of the mitogen-activated protein (MAP) kinase and Akt kinase pathways required for translation dependent phase of LTP are reduced. Our data suggest that loss or even the reduction of IRSp53 increases NMDAR dependent CREB activation in the hippoCAMPus, and interferes with the ability of mice to learn upon anxiety-related stimuli. This article is protected by copyright. All rights reserved. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 208 | J. Neurosci. 2015 Sep 35: 13148-59 |
| PMID | 26400944 |
| Title | Phosphorylation by PKA and Cdk5 Mediates the Early Effects of Synapsin III in Neuronal Morphological Maturation. |
| Abstract | Synapsin III (SynIII) is a neuron-specific phosphoprotein that plays a unique role in neuronal development. SynIII is phosphorylated by CAMP-dependent protein kinase (PKA) at a highly conserved phosphorylation site and by cyclin-dependent kinase-5 (Cdk5) at a newly described site. Although SynIII is known to be involved in axon elongation in vitro, the role of its phosphorylation by PKA and Cdk5 in the modulation of this process is unknown. We expressed either wild-type (WT) or phosphorylation-site mutants of SynIII in primary SynIII knock-out (KO) mouse neurons at early stages of in vitro development. Whereas the neurite elongation phenotype of SynIII KO neurons was fully rescued by the expression of WT SynIII, the expression of nonphosphorylatable and pseudo-phosphorylated PKA mutants was ineffective. Also, the nonphosphorylatable Cdk5 mutant was unable to rescue the neurite elongation phenotype of SynIII KO neurons. By contrast, the pseudo-phosphorylated mutant rescued the delay in neuronal maturation and axonal elongation, revealing a Cdk5-dependent regulation of SynIII function. Interestingly, SynIII KO neurons also exhibited decreased survival that was fully rescued by the expression of WT SynIII, but not by its phosphorylation mutants, and was associated with increased activated caspase3 and altered tropomyosin receptor kinase B isoform expression. These results indicate that PKA and Cdk5 phosphorylation is required for the physiological action of SynIII on axon specification and neurite outgrowth and that the expression of a functional SynIII is crucial for cell survival. Significance statement: Synapsin III is an atypical member of the synapsin family of synaptic vesicle-associated phosphoproteins that is precociously expressed in neurons and is downregulated afterward. Although experimental evidence suggests a specific role for Synapsin III in neuronal development, the molecular mechanisms are still largely unknown. We found that Synapsin III plays a central role in early stages of neuronal development involving neuronal survival, polarization, and neuritic growth and that these effects are dependent on phosphorylation by CAMP-dependent protein kinase and cyclin-dependent protein kinase-5. These results explain the recently described neurodevelopmental defects in the migration and orientation of Synapsin III-depleted cortical neurons and support the potential association of Synapsin III with neurodevelopmental disorders such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 209 | Eur Neuropsychopharmacol 2015 Nov 25: 2049-61 |
| PMID | 26372541 |
| Title | Trace amine-associated receptor 1 activation silences GSK3? signaling of TAAR1 and D2R heteromers. |
| Abstract | Trace amine-associated receptor 1 (TAAR1) activation by selective endogenous agonists modulates dopaminergic neurotransmission. This results in antipsychotic-like behavior in vivo which might be initiated by an interaction of TAAR1 and dopamine D2L receptor (D2R). Here we analyzed the functional link between TAAR1 and D2R using highly potent and selective TAAR1 agonists, and newly generated tools such as TAAR1 knock-out and TAAR1 overexpressing rats as well as specific anti-rat TAAR1 antibodies. We provide data from co-immunoprecipitation experiments supporting a functional interaction of the two receptors in heterologous cells and in brain tissue. Interaction of TAAR1 with D2R altered the subcellular localization of TAAR1 and increased D2R agonist binding affinity. Using specific ?-arrestin 2 (?Arr2) complementation assays we show that the interaction of TAAR1 with D2R reduced ?Arr2 recruitment to D2R. In addition, we report that besides G?s-protein signaling TAAR1 also signals via ?Arr2. In the presence of D2R, CAMP signaling of TAAR1 was reduced while its ?Arr2 signaling was enhanced, resulting in reduced GSK3? activation. These results demonstrate that ?Arr2 signaling may be an important pathway for TAAR1 function and that the activation of the TAAR1-D2R complex negatively modulates GSK3? signaling. Given that patients with schizophrenia or bipolar disorder show increased GSK3? signaling, such a reduction of GSK3? signaling triggered by the interaction of D2R with activated TAAR1 further supports TAAR1 as a target for the treatment of psychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 210 | PLoS ONE 2015 -1 10: e0132722 |
| PMID | 26162083 |
| Title | Unique Effects of Acute Aripiprazole Treatment on the Dopamine D2 Receptor Downstream cAMP-PKA and Akt-GSK3? Signalling Pathways in Rats. |
| Abstract | Aripiprazole is a wide-used antipsychotic drug with therapeutic effects on both positive and negative symptoms of schizophrenia, and reduced side-effects. Although aripiprazole was developed as a dopamine D2 receptor (D2R) partial agonist, all other D2R partial agonists that aimed to mimic aripiprazole failed to exert therapeutic effects in clinic. The present in vivo study aimed to investigate the effects of aripiprazole on the D2R downstream CAMP-PKA and Akt-GSK3? signalling pathways in comparison with a D2R antagonist--haloperidol and a D2R partial agonist--bifeprunox. Rats were injected once with aripiprazole (0.75 mg/kg, i.p.), bifeprunox (0.8 mg/kg, i.p.), haloperidol (0.1 mg/kg, i.p.) or vehicle. Five brain regions--the prefrontal cortex (PFC), nucleus accumbens (NAc), caudate putamen (CPu), ventral tegmental area (VTA) and substantia nigra (SN) were collected. The protein levels of PKA, Akt and GSK3? were measured by Western Blotting; the CAMP levels were examined by ELISA tests. The results showed that aripiprazole presented similar acute effects on PKA expression to haloperidol, but not bifeprunox, in the CPU and VTA. Additionally, aripiprazole was able to increase the phosphorylation of GSK3? in the PFC, NAc, CPu and SN, respectively, which cannot be achieved by bifeprunox and haloperidol. These results suggested that acute treatment of aripiprazole had differential effects on the CAMP-PKA and Akt-GSK3? signalling pathways from haloperidol and bifeprunox in these brain areas. This study further indicated that, by comparison with bifeprunox, the unique pharmacological profile of aripiprazole may be attributed to the relatively lower intrinsic activity at D2R. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 211 | J Mol Psychiatry 2015 -1 3: 7 |
| PMID | 26137221 |
| Title | Insights into the origin of DNA methylation differences between monozygotic twins discordant for schizophrenia. |
| Abstract | DNA methylation differences between monozygotic twins discordant for schizophrenia have been previously reported. However, the origin of methylation differences between monozygotic twins discordant for schizophrenia is not clear. The findings here argue that all DNA methylation differences may not necessarily represent the cause of the disease; rather some may result from the effect of antipsychotics. Methylation differences in rat brain regions and also in two pairs of unrelated monozygotic twins discordant for schizophrenia have been studied using genome-wide DNA methylation arrays at Arraystar Inc. (Rockville, Maryland, USA). The identified gene promoters showing significant alterations to DNA methylation were then further characterized using ingenuity pathway analysis (Ingenuity System Inc, CA, USA). Pathway analysis of the most significant gene promoter hyper/hypomethylation revealed a significant enrichment of DNA methylation changes in biological networks and pathways directly relevant to neural development and psychiatric disorders. These included HIPPO signaling (p?=?3.93E-03) and MAPK signaling (p?=?4.27E-03) pathways involving hypermethylated genes in schizophrenia-affected patients as compared to their unaffected co-twins. Also, a number of significant pathways and networks involving genes with hypomethylated gene promoters have been identified. These included CREB signaling in neurons (p?=?1.53E-02), Dopamine-DARPP32 feedback in CAMP signaling (p?=?7.43E-03) and Ephrin receptors (p?=?1.13E-02). Further, there was significant enrichment for pathways involved in nervous system development and function (p?=?1.71E-03-4.28E-02). The findings highlight the significance of antipsychotic drugs on DNA methylation in schizophrenia patients. The unique pathways affected by DNA methylation in the two pairs of monozygotic twins suggest that patient-specific pathways are responsible for the disease; suggesting that patient-specific treatment strategies may be necessary in treating the disorder. The study reflects the need for developing personalized medicine approaches that take into consideration epigenetic variations between patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 212 | Curr. Pharm. Des. 2015 -1 21: 3813-28 |
| PMID | 26044976 |
| Title | Treatment of Cognitive Impairment in Schizophrenia: Potential Value of Phosphodiesterase Inhibitors in Prefrontal Dysfunction. |
| Abstract | No pharmacological treatment is available to date that shows satisfactory effects on cognitive symptoms in patients diagnosed with schizophrenia. Phosphodiesterase inhibitors (PDE-Is) improve neurotransmitter signaling by interfering in intracellular second messenger cascades. By preventing the breakdown of CAMP and/or cGMP, central neurotransmitter activity is maintained. Different PDE families exist with distinct characteristics among which substrate specificity and regional distribution. Preclinical data is promising especially with regard to inhibition of PDE2, PDE4, PDE5 and PDE10. In addition, cognitive improvement has been reported in both elderly and/or non-impaired young human subjects after PDE1 or PDE4 inhibition. Moreover, some of these studies show effects on cognitive domains relevant to schizophrenia, in particular memory. The current review incorporates an overview of the distinct molecular characteristics of the different PDE families and their relationship to the neurobiological mechanisms related to cognitive dysfunction in schizophrenia. So far, procognitive effects of only three types of PDE-Is have been assessed in patients diagnosed with schizophrenia inhibiting PDE3, PDE5 and PDE10. However, the limited data available do not allow to draw firm conclusions on the value of PDE-Is as cognitive enhancers in schizophrenia yet. The field is still in its infancy, but nevertheless different PDE-Is seem promising as candidate to optimise neural communication in the prefrontal cortex favouring cognitive functioning in patients diagnosed with schizophrenia, in particular dual inhibitors including PDE1-Is, PDE3-Is and PDE10A-Is. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 213 | Gen. Physiol. Biophys. 2015 Jul 34: 277-84 |
| PMID | 25926551 |
| Title | Association analysis of PDE4B polymorphisms with schizophrenia and smooth pursuit eye movement abnormality in a Korean population. |
| Abstract | schizophrenia is a debilitating mental disorder with a high heritability rate. Located on chromosome 1p31.3, the human CAMP-specific 3',5'-cyclic phosphodiesterase 4B (PDE4B) gene has been considered as an important candidate gene for the risk of schizophrenia. Several genetic association studies reported the association between PDE4B polymorphisms and the risk of schizophrenia in Caucasian, African American, Indian, and Japanese populations. The aim of this study is to examine the association of PDE4B variations with schizophrenia and smooth pursuit eye movement (SPEM) abnormality in a Korean population. A case-control association analysis was carried out by comparing the genotype distribution of eight PDE4B polymorphisms between 457 schizophrenia patients and 386 normal healthy subjects. Differences in the frequency distribution of PDE4B single nucleotide polymorphisms (SNPs) and haplotypes were analyzed by logistic regression analyses controlling for age as a covariate. Statistical analyses revealed nominal significant associations of rs1040716, rs472952, rs1321177, and rs2144719 with the risk of schizophrenia (p = 0.02~0.05). The rs11208756 polymorphism showed a nominal significant association with SPEM abnormality (p = 0.05). In a meta-analysis with Japanese and Korean populations, three SNPs (rs472952, rs1040716, and rs2180335) revealed significant associations with schizophrenia (meta-p value = 0.0038~0.019). Our results support previously reported association of PDE4B variations with schizophrenia in other populations. The findings in this study add a new evidence for the involvement of PDE4B gene in schizophrenia etiology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 214 | J. Neurosci. Res. 2015 Jul 93: 1045-55 |
| PMID | 25881750 |
| Title | The lactate receptor, G-protein-coupled receptor 81/hydroxycarboxylic acid receptor 1: Expression and action in brain. |
| Abstract | We have proposed that lactate is a "volume transmitter" in the brain and underpinned this by showing that the lactate receptor, G-protein-coupled receptor 81 (GPR81, also known as HCA1 or HCAR1), which promotes lipid storage in adipocytes, is also active in the mammalian brain. This includes the cerebral neocortex and the hippoCAMPus, where it can be stimulated by physiological concentrations of lactate and by the HCAR1 agonist 3,5-dihydroxybenzoate to reduce CAMP levels. Cerebral HCAR1 is concentrated on the postsynaptic membranes of excitatory synapses and also is enriched at the blood-brain barrier. In synaptic spines and in adipocytes, HCAR1 immunoreactivity is also located on subplasmalemmal vesicular organelles, suggesting trafficking to and from the plasma membrane. Through activation of HCAR1, lactate can act as a volume transmitter that links neuronal activity, cerebral blood flow, energy metabolism, and energy substrate availability, including a glucose- and glycogen-saving response. HCAR1 may contribute to optimizing the CAMP concentration. For instance, in the prefrontal cortex, excessively high CAMP levels are implicated in impaired cognition in old age, fatigue, stress, and schizophrenia and in the deposition of phosphorylated tau protein in Alzheimer's disease. HCAR1 could serve to ameliorate these conditions and might also act through downstream mechanisms other than CAMP. Lactate exits cells through monocarboxylate transporters in an equilibrating manner and through astrocyte anion channels activated by depolarization. In addition to locally produced lactate, lactate produced by exercising muscle as well as exogenous HCAR1 agonists, e.g., from fruits and berries, might activate the receptor on cerebral blood vessels and brain cells. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 215 | Neurochem. Int. 2015 Sep 88: 97-109 |
| PMID | 25863284 |
| Title | mGlu?-GABAB interplay in animal models of positive, negative and cognitive symptoms of schizophrenia. |
| Abstract | Diverse preclinical studies exploiting the modulation of the GABAergic and/or glutamatergic system in brain via metabotropic receptors suggest their potential therapeutic utility. GS39783 and CDPPB, positive allosteric modulators of GABAB and mGlu5 receptors, were previously shown to reverse behavioral phenotypes in animal models to mimic selected (predominantly positive) symptoms of schizophrenia. In the present study we investigated the activity of selected GABAB (GS39783 and CGP7930) and mGlu5 (CDPPB) positive allosteric modulators. We focused mainly on the aspects of their efficacy in the models of negative and cognitive symptoms of schizophrenia. We used modified swim test, social interactions (models of negative symptoms) and novel object recognition (model of cognitive disturbances). The activity of the compounds was also tested in haloperidol-induced catalepsy test. The mutual interaction between GABAB/mGlu5 ligands was investigated as well. In the second part of the study, DHPG-induced PI hydrolysis in the presence of GABAB receptor antagonist (SKF97541), and SKF97541-induced inhibition of CAMP formation in the presence of DHPG, was performed. Both mGlu5 and GABAB receptor modulators effectively reversed MK-801-induced deficits in behavioral models of schizophrenia. Moreover, the concomitant administration of sub-effective doses of CDPPB and GS39783 induced a clear antipsychotic-like effect in all the procedures used, except DOI-induced head twitches. The concomitant administration of group I mGlu and GABAB agonists did not displayed any synergistic effects in vitro. Summing up, an activation of both types of receptor may be a promising mechanism for the development of novel antipsychotic drugs, efficacious toward positive, negative and cognitive symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 216 | Sci Rep 2015 -1 5: 8902 |
| PMID | 25754735 |
| Title | Paliperidone and aripiprazole differentially affect the strength of calcium-secretion coupling in female pituitary lactotrophs. |
| Abstract | Hyperprolactinemia is a common adverse in vivo effect of antipsychotic medications that are used in the treatment of patients with schizophrenia. Here, we compared the effects of two atypical antipsychotics, paliperidone and aripiprazole, on CAMP/calcium signaling and prolactin release in female rat pituitary lactotrophs in vitro. Dopamine inhibited spontaneous CAMP/calcium signaling and prolactin release. In the presence of dopamine, paliperidone rescued CAMP/calcium signaling and prolactin release in a concentration-dependent manner, whereas aripiprazole was only partially effective. In the absence of dopamine, paliperidone stimulated CAMP/calcium signaling and prolactin release, whereas aripiprazole inhibited signaling and secretion more potently but less effectively than dopamine. Forskolin-stimulated CAMP production was facilitated by paliperidone and inhibited by aripiprazole, although the latter was not as effective as dopamine. None of the compounds affected prolactin transcript activity, intracellular prolactin accumulation, or growth hormone secretion. These data indicate that paliperidone has dual hyperprolactinemic actions in lactotrophs i) by preserving the coupling of spontaneous electrical activity and prolactin secretion in the presence of dopamine and ii) by inhibiting intrinsic dopamine receptor activity in the absence of dopamine, leading to enhanced calcium signaling and secretion. In contrast, aripiprazole acts on prolactin secretion by attenuating, but not abolishing, calcium-secretion coupling. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 217 | Biol. Psychiatry 2015 Dec 78: 860-70 |
| PMID | 25731884 |
| Title | Stress Impairs Prefrontal Cortical Function via D1 Dopamine Receptor Interactions With Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels. |
| Abstract | Psychiatric disorders such as schizophrenia are worsened by stress, and working memory deficits are often a central feature of illness. Working memory is mediated by the persistent firing of prefrontal cortical (PFC) pyramidal neurons. Stress impairs working memory via high levels of dopamine D1 receptor (D1R) activation of cyclic adenosine monophosphate signaling, which reduces PFC neuronal firing. The current study examined whether D1R-cyclic adenosine monophosphate signaling reduces neuronal firing and impairs working memory by increasing the open state of hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels, which are concentrated on dendritic spines where PFC pyramidal neurons interconnect. A variety of methods were employed to test this hypothesis: dual immunoelectron microscopy localized D1R and HCN channels, in vitro recordings tested for D1R actions on HCN channel current, while recordings in monkeys performing a working memory task tested for D1R-HCN channel interactions in vivo. Finally, cognitive assessments following intra-PFC infusions of drugs examined D1R-HCN channel interactions on working memory performance. Immunoelectron microscopy confirmed D1R colocalization with HCN channels near excitatory-like synapses on dendritic spines in primate PFC. Mouse PFC slice recordings demonstrated that D1R stimulation increased HCN channel current, while local HCN channel blockade in primate PFC protected task-related firing from D1R-mediated suppression. D1R stimulation in rat or monkey PFC impaired working memory performance, while HCN channel blockade in PFC prevented this impairment in rats exposed to either stress or D1R stimulation. These findings suggest that D1R stimulation or stress weakens PFC function via opening of HCN channels at network synapses. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 218 | Neuroscience 2015 Apr 291: 189-202 |
| PMID | 25686523 |
| Title | Impramine, fluoxetine and clozapine differently affected reactivity to positive and negative stimuli in a model of motivational anhedonia in rats. |
| Abstract | Anhedonia is a relevant symptom in depression and schizophrenia. Chronic stress exposure induces in rats escape deficit, disrupts the dopaminergic response to palatable food and the competence to acquire sucrose self-administration (SA), thus configuring a possible model of motivational anhedonia. Repeated lithium administration reverts stress effects and brings back to control values the breaking point (BP) score, a measure of reward motivation. In this study, we tested on this model two antidepressants, imipramine and fluoxetine, and two antipsychotics, haloperidol and clozapine. The dopaminergic response to sucrose consumption was studied in non food-deprived rats in terms of dopamine D1 receptor signaling in the nucleus accumbens shell (NAcS). More specifically, we studied the modifications in dopamine and CAMP-regulated phosphoprotein of Mr 32,000 (DARPP-32) phosphorylation pattern following sucrose consumption. Fluoxetine reverted the escape deficit and showed no effects on dopaminergic response and sucrose SA. Imipramine reverted sucrose SA and dopamine response deficit in half of the rats and the escape deficit in all animals. Haloperidol did not affect stress-induced deficits. Clozapine-treated rats recovered the dopaminergic response to sucrose consumption and the competence to acquire sucrose SA, although they still showed the escape deficit, thus confirming that motivation toward reward may be dissociated from that to punishment escape. These results indicate that imipramine or fluoxetine are not endowed with a rapid onset antianhedonic effect. On the other hand, clozapine treatment showed a motivational antianhedonic activity similar to that observed after lithium treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 219 | Psychoneuroendocrinology 2015 Mar 53: 217-22 |
| PMID | 25637811 |
| Title | Oxytocin administration selectively improves olfactory detection thresholds for lyral in patients with schizophrenia. |
| Abstract | Olfaction plays an important role in mammalian social behavior. Olfactory deficits are common in schizophrenia and correlate with negative symptoms and low social drive. Despite their prominence and possible clinical relevance, little is understood about the pathological mechanisms underlying olfactory deficits in schizophrenia and there are currently no effective treatments for these deficits. The prosocial neuropeptide oxytocin may affect the olfactory system when administered intranasally to humans and there is growing interest in its therapeutic potential in schizophrenia. To examine this model, we administered 40IU of oxytocin and placebo intranasally to 31 patients with a schizophrenia spectrum illness and 34 age-matched healthy control participants in a randomized, double-blind, placebo-controlled, cross-over study. On each test day, participants completed an olfactory detection threshold test for two different odors: (1) lyral, a synthetic fragrance compound for which patients with schizophrenia have specific olfactory detection threshold deficits, possibly related to decreased cyclic adenosine 3',5'-monophosphate (CAMP) signaling; and (2) anise, a compound for which olfactory detection thresholds change with menstrual cycle phase in women. On the placebo test day, patients with schizophrenia did not significantly differ from healthy controls in detection of either odor. We found that oxytocin administration significantly and selectively improved olfactory detection thresholds for lyral but not for anise in patients with schizophrenia. In contrast, oxytocin had no effect on detection of either odor in healthy controls. Our data indicate that oxytocin administration may ameliorate olfactory deficits in schizophrenia and suggest the effects of intranasal oxytocin may extend to influencing the olfactory system. Given that oxytocin has been found to increase CAMP signaling in vitro a possible mechanism for these effects is discussed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 220 | CNS Neurosci Ther 2015 May 21: 446-53 |
| PMID | 25620115 |
| Title | Altered subcellular distribution of the 75-kDa DISC1 isoform, cAMP accumulation, and decreased neuronal migration in schizophrenia and bipolar disorder: implications for neurodevelopment. |
| Abstract | DISC1 (Disrupted-In-schizophrenia-1) is considered a genetic risk factor for schizophrenia (SZ) and bipolar disorder (BD). DISC1 regulates microtubule stability, migration, and CAMP signaling in mammalian cell lines and mouse brain tissue. CAMP is a regulator of microtubule organization and migration in neurons. Aberrant microtubule organization has been observed in olfactory neuronal precursors (ONP) derived from patients with SZ and BD, which suggests involvement of DISC1 and CAMP. However, the biology of DISC1 in the physiopathology of psychiatric conditions remains elusive. Herein, utilizing ONP obtained from SZ, BD patients and healthy subjects, we have studied DISC1 expression, protein levels, and subcellular distribution by qRT-PCR, immunoblotting, subcellular fractionation, and confocal microscopy. Cell migration and CAMP accumulation were assessed by Transwell and PKA competition assays. We found increased levels of the 75-kDa DISC1 isoform in total cell extracts of ONP from patients with SZ and BD compared with controls. Subcellular distribution showed a significant decrease of cytoplasmic DISC1 concomitant with its augmented levels in transcription sites. Moreover, significant CAMP accumulation and diminished migration were also observed in patients' cells. Alterations of DISC1 levels and its cellular distribution, which negatively modify CAMP homeostasis, microtubule organization, and cell migration, in ONP from patients with SZ and BD, suggest that their presence in early stages of brain development may impact brain maturation and function. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 221 | Psychopharmacology (Berl.) 2015 Jun 232: 2181-9 |
| PMID | 25575489 |
| Title | Reductions in synaptic proteins and selective alteration of prepulse inhibition in male C57BL/6 mice after postnatal administration of a VIP receptor (VIPR2) agonist. |
| Abstract | An abundance of genetic and epidemiologic evidence as well as longitudinal neuroimaging data point to developmental origins for schizophrenia and other mental health disorders. Recent clinical studies indicate that microduplications of VIPR2, encoding the vasoactive intestinal peptide (VIP) receptor VPAC2, confer significant risk for schizophrenia and autism spectrum disorder. Lymphocytes from patients with these mutations exhibited higher VIPR2 gene expression and VIP responsiveness (CAMP induction), but mechanisms by which overactive VPAC2 signaling may lead to these psychiatric disorders are unknown. We subcutaneously administered the highly selective VPAC2 receptor agonist Ro 25-1553 to C57BL/6 mice from postnatal day 1 (P1) to P14 to determine if overactivation of VPAC2 receptor signaling during postnatal brain maturation affects synaptogenesis and selected behaviors. Western blot analyses on P21 revealed significant reductions of synaptophysin and postsynaptic density protein 95 (PSD-95) in the prefrontal cortex, but not in the hippoCAMPus in Ro 25-1553-treated mice. The same postnatally restricted treatment resulted in a disruption in prepulse inhibition of the acoustic startle measured in adult mice. No effects were observed in open-field locomotor activity, sociability in the three-chamber social interaction test, or fear conditioning or extinction. Overactivation of the VPAC2 receptor in the postnatal mouse results in a reduction in synaptic proteins in the prefrontal cortex and selective alterations in prepulse inhibition. These findings suggest that the VIPR2-linkage to mental health disorders may be due in part to overactive VPAC2 receptor signaling during a critical time of synaptic maturation. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 222 | J. Pharmacol. Exp. Ther. 2015 Mar 352: 471-9 |
| PMID | 25525190 |
| Title | In vivo pharmacological characterization of TAK-063, a potent and selective phosphodiesterase 10A inhibitor with antipsychotic-like activity in rodents. |
| Abstract | Phosphodiesterase 10A (PDE10A) is a CAMP/cGMP phosphodiesterase highly expressed in medium spiny neurons (MSNs) in the striatum. We evaluated the in vivo pharmacological profile of a potent and selective PDE10A inhibitor, TAK-063 (1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)-pyridazin-4(1H)-one). TAK-063 at 0.3 and 1 mg/kg p.o., increased CAMP and cGMP levels in the rodent striatum and upregulated phosphorylation levels of key substrates of CAMP- and cGMP-dependent protein kinases. TAK-063 at 0.3 and 1 mg/kg p.o., strongly suppressed MK-801 [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine]-induced hyperlocomotion, which is often used as a predictive model for antipsychotic-like activity in rodents. Upregulation of striatal CAMP/cGMP levels and the antipsychotic-like effect of TAK-063 were not attenuated after 15 days of pretreatment with TAK-063 in mice. The potential side effect profile of TAK-063 was assessed in rats using the clinical antipsychotics haloperidol, olanzapine, and aripiprazole as controls. TAK-063 did not affect plasma prolactin or glucose levels at doses up to 3 mg/kg p.o. At 3 mg/kg p.o., TAK-063 elicited a weak cataleptic response compared with haloperidol and olanzapine. Evaluation of pathway-specific markers (substance P mRNA for the direct pathway and enkephalin mRNA for the indirect pathway) revealed that TAK-063 activated both the direct and indirect pathways of MSNs. These findings suggest that TAK-063 represents a promising drug for the treatment of schizophrenia with potential for superior safety and tolerability profiles. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 223 | Neurobiol Learn Mem 2015 Mar 119: 108-22 |
| PMID | 25464010 |
| Title | PDE and cognitive processing: beyond the memory domain. |
| Abstract | Phosphodiesterase inhibitors (PDE-Is) enhance CAMP and/or cGMP signaling via reducing the degradation of these cyclic nucleotides. Both CAMP and cGMP signaling are essential for a variety of cellular functions and exert their effects both pre- and post-synaptically. Either of these second messengers relays and amplifies incoming signals at receptors on the cell surface making them important elements in signal transduction cascades and essential in cellular signaling in a variety of cell functions including neurotransmitter release and neuroprotection. Consequently, these processes can be influenced by PDE-Is as they increase CAMP and/or cGMP concentrations. PDE-Is have been considered as possible therapeutic agents to treat impaired memory function linked to several brain disorders, including depression, schizophrenia and Alzheimer's disease (AD). This review will, however, focus on the possible role of phosphodiesterases (PDEs) in cognitive decline beyond the memory domain. Here we will discuss the involvement of PDEs on three related domains: attention, information filtering (sensory- and sensorimotor gating) and response inhibition (drug-induced hyperlocomotion). Currently, these are emerging cognitive domains in the field of PDE research. Here we discuss experimental studies and the potential beneficial effects of PDE-I drugs on these cognitive domains, as effects of PDE-Is on these domains could potentially influence effects on memory performance. Overall, PDE4 seems to be the most promising target for all domains discussed in this review. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 224 | Nucl. Med. Biol. 2015 Feb 42: 146-54 |
| PMID | 25451212 |
| Title | Characterization of the binding properties of T-773 as a PET radioligand for phosphodiesterase 10A. |
| Abstract | Phosphodiesterase 10A (PDE10A) is a dual-substrate PDE that hydrolyzes both CAMP and cGMP and is selectively expressed in striatal medium spiny neurons. Recent studies have suggested that PDE10A inhibition is a novel approach for the treatment of disorders such as schizophrenia and Huntington's disease. A positron emission tomography (PET) occupancy study can provide useful information for the development of PDE10A inhibitors. We discovered T-773 as a candidate PET radioligand for PDE10A and investigated its properties by in vitro autoradiography and a PET study in a monkey. Profiling of T-773 as a PET radioligand for PDE10A was conducted by in vitro enzyme inhibitory assay, in vitro autoradiography, and PET study in a monkey. T-773 showed a high binding affinity and selectivity for human recombinant PDE10A2 in vitro; the IC50 value in an enzyme inhibitory assay was 0.77nmol/L, and selectivity over other PDEs was more than 2500-fold. In autoradiography studies using mouse, rat, monkey, or human brain sections, radiolabeled T-773 selectively accumulated in the striatum. This selective accumulation was not observed in the brain sections of Pde10a-KO mice. The binding of [(3)H]T-773 to PDE10A in rat brain sections was competitively inhibited by MP-10, a selective PDE10A inhibitor. In rat brain sections, [(3)H]T-773 bound to a single high affinity site of PDE10A with Kd values of 12.2±2.2 and 4.7±1.2nmol/L in the caudate-putamen and nucleus accumbens, respectively. In a monkey PET study, [(11)C]T-773 showed good brain penetration and striatum-selective accumulation. These results suggest that [(11)C]T-773 is a potential PET radioligand for PDE10A. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 225 | Neurochem. Res. 2015 Feb 40: 380-8 |
| PMID | 25064045 |
| Title | Genetic dys-regulation of astrocytic glutamate transporter EAAT2 and its implications in neurological disorders and manganese toxicity. |
| Abstract | Astrocytic glutamate transporters, the excitatory amino acid transporter (EAAT) 2 and EAAT1 (glutamate transporter 1 and glutamate aspartate transporter in rodents, respectively), are the main transporters for maintaining optimal glutamate levels in the synaptic clefts by taking up more than 90% of glutamate from extracellular space thus preventing excitotoxic neuronal death. Reduced expression and function of these transporters, especially EAAT2, has been reported in numerous neurological disorders, including amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, schizophrenia and epilepsy. The mechanism of down-regulation of EAAT2 in these diseases has yet to be fully established. Genetic as well as transcriptional dys-regulation of these transporters by various modes, such as single nucleotide polymorphisms and epigenetics, resulting in impairment of their functions, might play an important role in the etiology of neurological diseases. Consequently, there has been an extensive effort to identify molecular targets for enhancement of EAAT2 expression as a potential therapeutic approach. Several pharmacological agents increase expression of EAAT2 via nuclear factor ?B and CAMP response element binding protein at the transcriptional level. However, the negative regulatory mechanisms of EAAT2 have yet to be identified. Recent studies, including those from our laboratory, suggest that the transcriptional factor yin yang 1 plays a critical role in the repressive effects of various neurotoxins, such as manganese (Mn), on EAAT2 expression. In this review, we will focus on transcriptional epigenetics and translational regulation of EAAT2. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 226 | Nutrition 2016 Feb 32: 174-8 |
| PMID | 26706021 |
| Title | Beneficial action of resveratrol: How and why? |
| Abstract | Flavonoid resveratrol modulates the transcription factor NF-?B; inhibits the cytochrome P450 isoenzyme CYP1 A1; suppresses the expression and activity of cyclooxygenase enzymes; and modulates Fas/Fas-ligand-mediated apoptosis, p53, mammalian target of rapamycin, and cyclins and various phosphodiesterases. This increases the cytosolic CAMP that activates Epac1/CaMKK?/AMPK/SIRT1/PGC-1? pathway, which in turn facilitates increased oxidation of fatty acids, mitochondrial biogenesis, mitochondrial respiration, and gluconeogenesis. Resveratrol triggers apoptosis of activated T cells and suppresses tumor necrosis factor-?, interluekin-17 (IL-17), and other proinflammatory molecules, and thus is of benefit in autoimmune diseases. In addition, resveratrol inhibits expression of hypoxia-inducible factor-1? and vascular endothelial growth factor, explaining its effective action against cancer. Brain-derived neurotrophic factor (BDNF) that is involved in the pathogenesis of obesity, type 2 diabetes mellitus, and metabolic syndrome is also altered in depression, schizophrenia, bipolar disorder, and autism. We noted that BDNF protects against cytotoxic actions of alloxan, streptozotocin, and benzo(a)pyrene. Resveratrol prevents bisphenol A-induced autism, type 2 diabetes mellitus, and metabolic syndrome, suggesting that it may augment BDNF synthesis and action. We also observed that BDNF levels are low in type 2 diabetes mellitus and that BDNF enhances production of antiinflammatory lipid, lipoxin A4, whose levels are low in diabetes mellitus. Thus, resveratrol may augment production of lipoxin A4. Resveratrol alters gut microbiota and influences stem cell proliferation and differentiation. These pleiotropic actions of resveratrol may explain the multitude of its actions and benefits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 227 | Curr Top Med Chem 2016 Apr -1: -1 |
| PMID | 27112214 |
| Title | Enhancing cAMP Levels as Strategy for the Treatment of Neuropsychiatric Disorders. |
| Abstract | Phosphodiesterases (PDEs) have gained increased attention as potential new targets for neuropsychiatric diseases due to their ability to hydrolyze the second messengers, cGMP and/or CAMP. It is well-known the relationship between CAMP signaling and inflammation. Since neuroinflammation is considered to play an important role in the pathology of brain disorders, inhibition of PDEs highly expressed in brain has emerged as an innovative strategy for the treatment of these pathologies. PDE4, 7, 8 and 10 inhibitors are presented here as promising drug candidates to overcome the partial efficacy and adverse effects of the current therapy for neuropsychiatric illness such as depression, cognitive impairments or schizophrenia. Enhancing the intracellular concentration of CAMP underlies the effects of PDE inhibitors in the above mentioned disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 228 | Schizophr. Res. 2016 Apr 172: 68-74 |
| PMID | 26899345 |
| Title | A network of synaptic genes associated with schizophrenia and bipolar disorder. |
| Abstract | Identification of novel candidate genes for schizophrenia (SZ) and bipolar disorder (BP), two psychiatric disorders with large epidemiological impacts, is a key research area in neurosciences and psychiatric genetics. Previous evidence from genome-wide studies suggests an important role for genes involved in synaptic plasticity in the risk for SZ and BP. We used a convergent genomics approach, combining different lines of biological evidence, to identify genes involved in the CAMP/PKA/CREB functional pathway that could be novel candidates for BP and SZ: CREB1, CREM, GRIN2C, NPY2R, NF1, PPP3CB and PRKAR1A. These 7 genes were analyzed in a HapMap based association study comprising 48 common SNPs in 486 SZ, 351 BP patients and 514 control individuals recruited from an isolated population in Northern Sweden. Genetic analysis showed significant allelic associations of SNPs in PRKAR1A with SZ and of PPP3CB and PRKAR1A with BP. Our results highlight the feasibility and the importance of convergent genomic data analysis for the identification of candidate genes and our data provide support for the role of common inherited variants in synaptic genes and their involvement in the etiology of BP and SZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 229 | Cell. Signal. 2016 Jul 28: 749-52 |
| PMID | 26432168 |
| Title | Uncovering the function of Disrupted in Schizophrenia 1 through interactions with the cAMP phosphodiesterase PDE4: Contributions of the Houslay lab to molecular psychiatry. |
| Abstract | Nearly 10years ago the laboratory of Miles Houslay was part of a collaboration which identified and characterized the interaction between Disrupted in schizophrenia 1 and phosphodiesterase type 4. This work has had significant impact on our thinking of psychiatric illness causation and the potential for therapeutics. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 230 | Front Neurosci 2016 -1 10: 148 |
| PMID | 27092049 |
| Title | Trace Amines and the Trace Amine-Associated Receptor 1: Pharmacology, Neurochemistry, and Clinical Implications. |
| Abstract | Biogenic amines are a collection of endogenous molecules that play pivotal roles as neurotransmitters and hormones. In addition to the "classical" biogenic amines resulting from decarboxylation of aromatic acids, including dopamine (DA), norepinephrine, epinephrine, serotonin (5-HT), and histamine, other biogenic amines, present at much lower concentrations in the central nervous system (CNS), and hence referred to as "trace" amines (TAs), are now recognized to play significant neurophysiological and behavioral functions. At the turn of the century, the discovery of the trace amine-associated receptor 1 (TAAR1), a phylogenetically conserved G protein-coupled receptor that is responsive to both TAs, such as ?-phenylethylamine, octopamine, and tyramine, and structurally-related amphetamines, unveiled mechanisms of action for TAs other than interference with aminergic pathways, laying the foundations for deciphering the functional significance of TAs and its mammalian CNS receptor, TAAR1. Although, its molecular interactions and downstream targets have not been fully elucidated, TAAR1 activation triggers accumulation of intracellular CAMP, modulates PKA and PKC signaling and interferes with the ?-arrestin2-dependent pathway via G protein-independent mechanisms. TAAR1 is uniquely positioned to exert direct control over DA and 5-HT neuronal firing and release, which has profound implications for understanding the pathophysiology of, and therefore designing more efficacious therapeutic interventions for, a range of neuropsychiatric disorders that involve aminergic dysregulation, including Parkinson's disease, schizophrenia, mood disorders, and addiction. Indeed, the recent development of novel pharmacological tools targeting TAAR1 has uncovered the remarkable potential of TAAR1-based medications as new generation pharmacotherapies in neuropsychiatry. This review summarizes recent developments in the study of TAs and TAAR1, their intricate neurochemistry and pharmacology, and their relevance for neurodegenerative and neuropsychiatric disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 231 | CNS Neurol Disord Drug Targets 2016 -1 15: 477-88 |
| PMID | 26996173 |
| Title | Global Expression Studies of Schizophrenic Brain: A Meta-Analysis Study Linking Neurological Immune System with Psychological Disorders. |
| Abstract | schizophrenia, a psychological disorder with enormous societal impact, is a result of abnormalities in gene expression and dysregulation of the immune response in the brain. Few studies have been conducted to understand its etiology, however, the exact molecular mechanism largely remains unknown, though some poorly understood theories abound. Present meta-study links the role of central nervous system, immunological system and psychological disorders by using global expression approach and pathway analysis. We retrieved genome-wide mRNA expression data and clinico-pathological information from five independent studies of schizophrenic patients from Gene Expression Omnibus database. We continued further with three studies having common platform. Our result showed a total of 527 differentially expressed genes of which 314 are up regulated and 213 are down regulated. After adjusting the sources of variation, we carried out pathway and gene ontology analysis, and observed alteration of 14-3-3-mediated signaling, ?-aminobutyric acid receptor signaling, role of nuclear factor of activated T-cells in regulation of the immune response, G beta gamma signaling, dopamine- and cyclic AMP-regulated phosphoprotein of relative molecular mass 32,000 feedback in CAMP signaling, complement system, axonal guidance signaling, dendritic cell maturation, CAMP response element-binding protein signaling in neurons and interleukin-1 signaling pathways and networks. Conclusively, our global gene expression pathway and gene set enrichment analysis studies suggest disruption of many common pathways and processes, which links schizophrenia to immune and central nervous system. Present meta-study links the role of central nervous system, immunological system and psychological disorders by using global expression approach and pathway analysis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 232 | J. Mol. Neurosci. 2016 May 59: 36-47 |
| PMID | 26894264 |
| Title | Aripiprazole Increases the PKA Signalling and Expression of the GABAA Receptor and CREB1 in the Nucleus Accumbens of Rats. |
| Abstract | The GABAA receptor is implicated in the pathophysiology of schizophrenia and regulated by PKA signalling. Current antipsychotics bind with D2-like receptors, but not the GABAA receptor. The CAMP-responsive element-binding protein 1 (CREB1) is also associated with PKA signalling and may be related to the positive symptoms of schizophrenia. This study investigated the effects of antipsychotics in modulating D2-mediated PKA signalling and its downstream GABAA receptors and CREB1. Rats were treated orally with aripiprazole (0.75 mg/kg, ter in die (t.i.d.)), bifeprunox (0.8 mg/kg, t.i.d.), haloperidol (0.1 mg/kg, t.i.d.) or vehicle for 1 week. The levels of PKA-C? and p-PKA in the prefrontal cortex (PFC), nucleus accumbens (NAc) and caudate putamen (CPu) were detected by Western blots. The mRNA levels of Gabrb1, Gabrb2, Gabrb3 and Creb1, and their protein expression were measured by qRT-PCR and Western blots, respectively. Aripiprazole elevated the levels of p-PKA and the ratio of p-PKA/PKA in the NAc, but not the PFC and CPu. Correlated with this elevated PKA signalling, aripiprazole elevated the mRNA and protein expression of the GABAA (?-1) receptor and CREB1 in the NAc. While haloperidol elevated the levels of p-PKA and the ratio of p-PKA/PKA in both NAc and CPu, it only tended to increase the expression of the GABAA (?-1) receptor and CREB1 in the NAc, but not the CPu. Bifeprunox had no effects on PKA signalling in these brain regions. These results suggest that aripiprazole has selective effects on upregulating the GABAA (?-1) receptor and CREB1 in the NAc, probably via activating PKA signalling. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 233 | J. Neurochem. 2016 May 137: 549-60 |
| PMID | 26876117 |
| Title | Dopamine D2 and serotonin 5-HT1A receptor interaction in the context of the effects of antipsychotics - in vitro studies. |
| Abstract | The serotonin 5-HT1A receptor (5-HT1 A R) and dopamine D2 receptor (D2 R) have been implicated as important sites of action in antipsychotics. Several lines of evidence indicate the key role of G protein-coupled receptors (GPCRs) heteromers in pathophysiology of schizophrenia and highlight these complexes as novel drug targets. Because heterodimers can form only on those cells co-expressing constituent receptors, they present a target of high pharmacological specificity in the context of biochemical effects induced by antipsychotic drugs. In studies conducted in the HEK 293 cell line, we demonstrated that 5-HT1 A R and D2 R are able to form constitutive heterodimers, and antipsychotic drugs (clozapine, olanzapine, aripiprazole, and lurasidone) enhanced this process, with clozapine being most effective. Various functional tests (CAMP and IP1 as well as ERK activation) indicated that the drugs had different effects on signal transduction by the heteromer. Interestingly, co-incubation of heterodimer-expressing HEK 293 cells with clozapine and the 5-HT1 A R agonist 8-OH DPAT potentiated post-synaptic effects, especially with respect to ERK activation. Our results indicate that the D2 -5-HT1A complex possesses biochemical, pharmacological, and functional properties distinct from those of mono- and homomers. This result has implications for the development of improved pharmacotherapy for schizophrenia or other disorders (activating the heteromer might be cognitive enhancing, since it is expressed in frontal cortex) through the specific targeting of heterodimers. We reported the constitutive formation of D2 -5-HT1A heteromers, which possess biochemical, pharmacological, and functional properties distinct from those of mono- and homomers, as revealed by antipsychotics action. We also showed that these two receptors are co-expressed in mouse cortical neurons; therefore their potential to heterodimerize may comprise an essential target for the development of novel strategies for schizophrenia treatment. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 234 | Oncotarget 2016 Feb -1: -1 |
| PMID | 26872373 |
| Title | DARPP-32: from neurotransmission to cancer. |
| Abstract | Dopamine and CAMP-regulated phosphoprotein Mr 32,000 (DARPP-32), also known as phosphoprotein phosphatase-1 regulatory subunit 1B (PPP1R1B), was initially discovered as a substrate of dopamine-activated protein kinase A (PKA) in the neostriatum in the brain. While phosphorylation at Thr-34 by PKA converts DARPP-32 into a potent inhibitor of protein phosphatase 1 (PP1), phosphorylation at Thr-75 transforms DARPP-32 into an inhibitor of PKA. Through regulation of DARPP-32 phosphorylation and modulation of protein phosphatase and kinase activities, DARPP-32 plays a critical role in mediating the biochemical, electrophysiological, and behavioral effects controlled by dopamine and other neurotransmitters in response to drugs of abuse and psychostimulants. Altered expression of DARPP-32 and its truncated isoform (t-DARPP), specifically in the prefrontal cortex, has been associated with schizophrenia and bipolar disorder. Moreover, cleavage of DARPP-32 by calpain has been implicated in Alzheimer's disease. Amplification of the genomic locus of DARPP-32 at 17q12 has been described in several cancers. DARPP-32 and t-DARPP are frequently overexpressed at the mRNA and protein levels in adenocarcinomas of the breast, prostate, colon, and stomach. Several studies demonstrated the pro-survival, pro-invasion, and pro-angiogenic functions of DARPP-32 in cancer. Overexpression of DARPP-32 and t-DARPP also promotes chemotherapeutic drug resistance and cell proliferation in gastric and breast cancers through regulation of pro-oncogenic signal transduction pathways. The expansion of DARPP-32 research from neurotransmission to cancer underscores the broad scope and implication of this protein in disparate human diseases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 235 | Biochimie 2016 Apr 123: 52-64 |
| PMID | 26805384 |
| Title | Investigating the structural impact of S311C mutation in DRD2 receptor by molecular dynamics & docking studies. |
| Abstract | Dopamine receptors (DR) are neuronal cell surface proteins that mediate the action of neurotransmitter dopamine in brain. Dopamine receptor D2 (DRD2) that belongs to G-protein coupled receptors (GPCR) family is a major therapeutic target for of various neurological and psychiatric disorders in human. The third inter cellular loop (ICL3) in DRD2 is essential for coupling G proteins and several signaling scaffold proteins. A mutation in ICL3 can interfere with this binding interface, thereby altering the DRD2 signaling. In this study we have examined the deleterious effect of serine to cysteine mutation at position 311 (S311C) in the ICL3 region that is implicated in diseases like schizophrenia and alcoholism. An in silico structure modeling approach was employed to determine the wild type (WT) and mutant S311C structures of DRD2, scaffold proteins - G?i/o and NEB2. Protein-ligand docking protocol was exercised to predict the interactions of natural agonist dopamine with both the WT and mutant structures of DRD2. Besides, atomistic molecular dynamics (MD) simulations were performed to provide insights into essential dynamics of the systems-unbound and dopamine bound DRD2 (WT and mutant) and three independent simulations for G?i, G?o and NEB2 systems. To provide information on intra-molecular arrangement of the structures, a comprehensive residue interactions network of both dopamine bound WT and mutant DRD2 protein were studied. We also employed a protein-protein docking strategy to find the interactions of scaffold proteins - G?i/o and NEB2 with both dopamine bound WT and mutant structures of DRD2. We observed a marginal effect of the mutation in dopamine binding mechanism on the trajectories analyzed. However, we noticed a significant structural alteration of the mutant receptor which affects G?i/o and NEB2 binding that can be causal for malfunctioning in CAMP-dependent signaling and Ca(+) homeostasis in the brain dopaminergic system leading to neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 236 | Oncotarget 2016 Feb 7: 5353-65 |
| PMID | 26713600 |
| Title | ?-catenin nuclear translocation in colorectal cancer cells is suppressed by PDE10A inhibition, cGMP elevation, and activation of PKG. |
| Abstract | Phosphodiesterase 10A (PDE10) is a cGMP and CAMP degrading PDE isozyme that is highly expressed in the brain striatum where it appears to play an important role in cognition and psychomotor activity. PDE10 inhibitors are being developed for the treatment of schizophrenia and Huntington's disease and are generally well tolerated, possibly because of low expression levels in most peripheral tissues. We recently reported high levels of PDE10 in colon tumors and that genetic silencing of PDE10 by siRNA or inhibition with small molecule inhibitors can suppress colon tumor cell growth with a high degree of selectivity over normal colonocytes (Li et al., Oncogene 2015). These observations suggest PDE10 may have an unrecognized role in tumorigenesis. Here we report that the concentration range by which the highly specific PDE10 inhibitor, Pf-2545920 (MP-10), inhibits colon tumor cell growth parallels the concentration range required to increase cGMP and CAMP levels, and activates PKG and PKA, respectively. Moreover, PDE10 knockdown by shRNA reduces the sensitivity of colon tumor cells to the growth inhibitory activity of Pf-2545920. Pf-2545920 also inhibits the translocation of ?-catenin to the nucleus, thereby reducing ?-catenin mediated transcription of survivin, resulting in caspase activation and apoptosis. PDE10 mRNA was also found to be elevated in colon tumors compared with normal tissues. These findings suggest that PDE10 can be targeted for cancer therapy or prevention whereby inhibition results in cGMP elevation and PKG activation to reduce ?-catenin-mediated transcription of survival proteins leading to the selective apoptosis of cancer cells. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 237 | J. Neurochem. 2016 Mar 136: 1037-51 |
| PMID | 26685100 |
| Title | Dysbindin-1 modifies signaling and cellular localization of recombinant, human D3 and D2 receptors. |
| Abstract | Dystrobrevin binding protein-1 (dysbindin-1), a candidate gene for schizophrenia, modulates cognition, synaptic plasticity and frontocortical circuitry and interacts with glutamatergic and dopaminergic transmission. Loss of dysbindin-1 modifies cellular trafficking of dopamine (DA) D2 receptors to increase cell surface expression, but its influence upon signaling has never been characterized. Further, the effects of dysbindin-1 upon closely related D3 receptors remain unexplored. Hence, we examined the impact of dysbindin-1 (isoform A) co-expression on the localization and coupling of human D2L and D3 receptors stably expressed in Chinese hamster ovary or SH-SY5Y cells lacking endogenous dysbindin-1. Dysbindin-1 co-transfection decreased cell surface expression of both D3 and D2L receptors. Further, while their affinity for DA was unchanged, dysbindin-1 reduced the magnitude and potency of DA-induced adenylate cylase recruitment/CAMP production. Dysbindin-1 also blunted the amplitude of DA-induced phosphorylation of ERK1/2 and Akt at both D2L and D3 receptors without, in contrast to CAMP, affecting the potency of DA. Interference with calveolin/clathrin-mediated processes of internalization prevented the modification by dysbindin-1 of ERK1/2 and adenylyl cyclase stimulation at D2L and D3 receptors. Finally, underpinning the specificity of the influence of dysbindin-1 on D2L and D3 receptors, dysbindin-1 did not modify recruitment of adenylyl cyclase by D1 receptors. These observations demonstrate that dysbindin-1 influences cell surface expression of D3 in addition to D2L receptors, and that it modulates activation of their signaling pathways. Accordingly, both a deficiency and an excess of dysbindin-1 may be disruptive for dopaminergic transmission, supporting its link to schizophrenia and other CNS disorders. Dysbindin-1, a candidate gene for schizophrenia, alters D2 receptors cell surface expression. We demonstrate that dysbindin-1 expression also influences cell surface levels of D3 receptors. Further, Dysbindin-1 reduces DA-induced adenylate cylase recruitment/CAMP production and modifies major signaling pathways (Akt and extracellular signal-regulated kinases1/2 (ERK1/2)) of both D2 and D3 receptors. Dysbindin-1 modulates thus D2 and D3 receptor signaling, supporting a link to schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 238 | Behav Pharmacol 2016 Jun 27: 331-8 |
| PMID | 26580130 |
| Title | The effects of PDE10 inhibition on attentional set-shifting do not depend on the activation of dopamine D1 receptors. |
| Abstract | Inhibitors of phosphodiesterase 10A (PDE10A) represent a novel class of potential antipsychotic compounds. These principles increase the level of CAMP and cGMP in the medium spiny neurons of the striatum and resemble the neurochemical consequences of dopamine D2 receptor inhibition and dopamine D1 receptor stimulation. Cognitive dysfunctions, including an impaired ability to shift perceptual attentional set, are core features of schizophrenia. In the present study, we investigated the involvement of D1 receptors in the procognitive action of the PDE10A inhibitor using the attentional set-shifting task in rats. The performance of the rats in the extradimensional shift stage of the attentional set-shifting task was taken as an index of cognitive flexibility. We first assessed the effects of the D1 agonist in otherwise untreated animals and in animals pretreated with the D1 receptor antagonist. We then investigated the procognitive effects of the PDE10A inhibitor, MP-10, in otherwise untreated animals and in animals pretreated with the D1 receptor antagonist. The dopamine D1 receptor antagonist SCH-23390 produced cognitive impairment at the dose of 0.0125?mg/kg, but not at 0.0063?mg/kg. The D1 receptor agonist, SKF-81,297, produced a procognitive effect that was abolished by 0.0063?mg/kg of SCH-23390. The compound MP-10 produced a procognitive effect at the dose of 0.3?mg/kg, but not at 0.1?mg/kg. Rat pretreatment with 0.0063?mg/kg of SCH-23390 did not block the procognitive effect of 0.3?mg/kg of MP-10. The present study demonstrates that the blockade of dopamine D1 receptors is unlikely to affect the procognitive effects of PDE10A inhibition. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 239 | Neuropsychopharmacology 2016 Mar 41: 1080-92 |
| PMID | 26272049 |
| Title | Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition. |
| Abstract | Cognitive dysfunction is a core feature of dementia and a prominent feature in psychiatric disease. As non-redundant regulators of intracellular CAMP gradients, phosphodiesterases (PDE) mediate fundamental aspects of brain function relevant to learning, memory, and higher cognitive functions. Phosphodiesterase-4B (PDE4B) is an important phosphodiesterase in the hippoCAMPal formation, is a major Disrupted in schizophrenia 1 (DISC1) binding partner and is itself a risk gene for psychiatric illness. To define the effects of specific inhibition of the PDE4B subtype, we generated mice with a catalytic domain mutant form of PDE4B (Y358C) that has decreased ability to hydrolyze CAMP. Structural modeling predictions of decreased function and impaired binding with DISC1 were confirmed in cell assays. Phenotypic characterization of the PDE4B(Y358C) mice revealed facilitated phosphorylation of CREB, decreased binding to DISC1, and upregulation of DISC1 and ?-Arrestin in hippoCAMPus and amygdala. In behavioral assays, PDE4B(Y358C) mice displayed decreased anxiety and increased exploration, as well as cognitive enhancement across several tests of learning and memory, consistent with synaptic changes including enhanced long-term potentiation and impaired depotentiation ex vivo. PDE4B(Y358C) mice also demonstrated enhanced neurogenesis. Contextual fear memory, though intact at 24?h, was decreased at 7 days in PDE4B(Y358C) mice, an effect replicated pharmacologically with a non-selective PDE4 inhibitor, implicating CAMP signaling by PDE4B in a very late phase of consolidation. No effect of the PDE4B(Y358C) mutation was observed in the prepulse inhibition and forced swim tests. Our data establish specific inhibition of PDE4B as a promising therapeutic approach for disorders of cognition and anxiety, and a putative target for pathological fear memory. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 240 | J. Clin. Lab. Anal. 2016 May 30: 196-9 |
| PMID | 25546171 |
| Title | Expression of Phosphodiesterase 4B cAMP-Specific Gene in Subjects With Cryptorchidism and Down's Syndrome. |
| Abstract | Cryptorchidism represents a risk factor for infertility and germ cell testicular neoplasia. An increased rate of cryptorchidism has been reported in subjects with Down's syndrome. Cyclic nucleotide phosphodiesterases (PDEs) are important messengers that regulate and mediate a number of cellular responses to extracellular signals, such as neurotransmitters and hormones. PDE4B, CAMP-specific (PDE4B) gene which maps to chromosome 1p31.3 appears to be involved in schizophrenia, chronic psychiatric illness, learning, memory, and mood disturbances. Expression of PDE4 enzymes have been studied in testes of cryptorchid rats. Expression of PDE4B protein examination showed marked degenerative changes in the epithelial lining of the seminiferous tubules. These findings led us to evaluate PDE4 mRNA expression in leukocytes of peripheral blood of five men with DS and cryptorchidism and eleven subjects with DS without cryptorchidism compared with healthy men (controls) by quantitative Real Time PCR (qRT-PCR). This study showed that the PDE4B gene was downexpressed in men with DS and cryptorchidism compared to normal controls and DS without cryptorchidism. A lower expression of the PDE4B gene may be involved in the neurological abnormalities in subjects with Down's syndrome. Moreover, PDE4B gene may be involved in the testicular abnormalities of men with DS and cryptorchidism. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 241 | CNS Neurol Disord Drug Targets 2016 -1 15: 477-88 |
| PMID | 26996173 |
| Title | Global Expression Studies of Schizophrenic Brain: A Meta-Analysis Study Linking Neurological Immune System with Psychological Disorders. |
| Abstract | schizophrenia, a psychological disorder with enormous societal impact, is a result of abnormalities in gene expression and dysregulation of the immune response in the brain. Few studies have been conducted to understand its etiology, however, the exact molecular mechanism largely remains unknown, though some poorly understood theories abound. Present meta-study links the role of central nervous system, immunological system and psychological disorders by using global expression approach and pathway analysis. We retrieved genome-wide mRNA expression data and clinico-pathological information from five independent studies of schizophrenic patients from Gene Expression Omnibus database. We continued further with three studies having common platform. Our result showed a total of 527 differentially expressed genes of which 314 are up regulated and 213 are down regulated. After adjusting the sources of variation, we carried out pathway and gene ontology analysis, and observed alteration of 14-3-3-mediated signaling, ?-aminobutyric acid receptor signaling, role of nuclear factor of activated T-cells in regulation of the immune response, G beta gamma signaling, dopamine- and cyclic AMP-regulated phosphoprotein of relative molecular mass 32,000 feedback in CAMP signaling, complement system, axonal guidance signaling, dendritic cell maturation, CAMP response element-binding protein signaling in neurons and interleukin-1 signaling pathways and networks. Conclusively, our global gene expression pathway and gene set enrichment analysis studies suggest disruption of many common pathways and processes, which links schizophrenia to immune and central nervous system. Present meta-study links the role of central nervous system, immunological system and psychological disorders by using global expression approach and pathway analysis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |