| 1 | J. Mol. Endocrinol. 2005 Jun 34: 835-48 |
|---|---|
| PMID | 15956351 |
| Title | TRAP220 is modulated by the antineoplastic agent 6-Mercaptopurine, and mediates the activation of the NR4A subgroup of nuclear receptors. |
| Abstract | The NR4A1-3 (Nur77, NURR1 and NOR-1) subfamily of nuclear hormone receptors (NRs) has been implicated in Parkinson's disease, schizophrenia, manic depression, atherogenesis, Alzheimer's disease, rheumatoid arthritis, cancer and apoptosis. This has driven investigations into the mechanism of action, and the identification of small molecule regulators, that may provide the platform for pharmaceutical and therapeutic exploitation. Recently, we found that the purine antimetabolite 6-Mercaptopurine (6-MP), which is widely used as an anti-neoplastic and anti-inflammatory drug, modulated the NR4A1-3 subfamily. Interestingly, the agonist-mediated activation did not involve modulation of primary coactivators' (e.g. p300 and SRC-2/GRIP-1) activity and/or recruitment. However, the role of the subsequently recruited coactivators, for example CARM-1 and TRAP220, in 6-MP-mediated activation of the NR4A1-3 subfamily remains obscure. In this study we demonstrate that 6-MP modulates the activity of the coactivator TRAP220 in a dose-dependent manner. Moreover, we demonstrate that TRAP220 potentiates NOR-1-mediated transactivation, and interacts with the NR4A1-3 subgroup in an AF-1-dependent manner in a cellular context. The region of TRAP220 that mediated 6-MP activation and NR4A interaction was delimited to amino acids 1-800, and operates independently of the critical PKC and PKA phosphorylation sites. Interestingly, TRAP220 expression does not increase the relative induction by 6-MP, however the absolute level of NOR-1-mediated trans-activation is increased. This study demonstrates that 6-MP modulates the activity of the NR4A subgroup, and the coactivator TRAP220. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | J. Pharmacol. Exp. Ther. 2005 May 313: 594-603 |
| PMID | 15659539 |
| Title | Clozapine potentiation of N-methyl-D-aspartate receptor currents in the nucleus accumbens: role of NR2B and protein kinase A/Src kinases. |
| Abstract | Clozapine is an atypical antipsychotic that has a unique clinical profile that distinguishes it from other typical and atypical antipsychotics. At present, the underlying mechanisms of action of clozapine are unclear. Recent studies in the field of schizophrenia suggest that compounds that potentiate N-methyl-d-aspartate (NMDA) receptor function in the appropriate brain regions might be an effective antipsychotic agent. One relevant region in which NMDA receptors play a key role in mediating neurotransmission is the nucleus accumbens. Therefore, we investigated the regulation of NMDA receptor currents and excitatory postsynaptic currents (EPSCs) by clozapine in nucleus accumbens neurons. Whole-cell patch-clamp recordings were performed in rat brain slices. We demonstrate that bath application of clozapine but not haloperidol or the selective 5-hydroxytryptamine 2A antagonist MDL100907 [(R)-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluoro-phenyl)ethyl]-4-piperidine methanol] induces a robust potentiation of NMDA-evoked currents and of glutamatergic EPSCs and that this potentiation is dependent on dopamine release and postsynaptic activation of D1 receptors. Furthermore, the effect of clozapine is selective for NR2B subtype-containing NMDA receptors and is blocked by the selective SRC family kinase inhibitor PP2 [4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine] and the protein kinase A-selective inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide but not by the protein kinase C-selective inhibitor bisindolylmaleimide I. This effect of clozapine in the nucleus accumbens might underlie the unique clinical profile of this atypical antipsychotic and provides a basis for novel treatment approaches. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Neuropsychopharmacology 2006 Jul 31: 1420-30 |
| PMID | 16123741 |
| Title | Atypical antipsychotics and a Src kinase inhibitor (PP1) prevent cortical injury produced by the psychomimetic, noncompetitive NMDA receptor antagonist MK-801. |
| Abstract | Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine, ketamine, and MK-801 produce schizophrenia-like psychosis in humans. The same NMDA antagonists injure retrosplenial cortical neurons in adult rats. We examined the effects of atypical antipsychotics and an inhibitor of nonreceptor tyrosine kinase pp60 (SRC) on the cortical injury produced by MK-801. An atypical antipsychotic (either clozapine, ziprasidone, olanzapine, quetiapine, or risperidone) or vehicle was administered to adult female Sprague-Dawley rats. PP1 (SRC inhibitor), PP3 (nonfunctional analog of PP1) or vehicle (DMSO) was administered to another group of animals. After pretreatment, animals were injected with MK-801, killed 24 h after the MK-801, and injury to retrosplenial cortex assessed by neuronal Hsp70 protein expression. All atypical antipsychotics examined significantly attenuated MK-801-induced cortical damage. PP1 protected compared to vehicle, whereas PP3 did not protect. The ED50s (decrease injury by 50%) were as follows: PP1 <0.1 mg/kg; olanzapine 0.8 mg/kg; risperdal 1 mg/kg; clozapine 3 mg/kg; ziprasidone 32 mg/kg; and quetiapine 45 mg/kg. The data show that the atypical antipsychotics tested as well as a SRC kinase inhibitor prevent the injury produced by the psychomimetic MK-801, and the potency of the atypical antipsychotics for preventing cortical injury was roughly similar to the potency of these drugs for treating psychosis in patients. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Psychiatr. Genet. 2007 Jun 17: 201-4 |
| PMID | 17417065 |
| Title | Polymorphisms of the Fyn kinase gene and a performance on the Wisconsin Card Sorting Test in schizophrenia. |
| Abstract | The glutamatergic system has been implicated in the pathogenesis and prefrontal cortex dysfunctions in schizophrenia. The SRC-family tyrosine kinase Fyn plays a key role in the interaction between brain-derived neurotrophic factor and glutamatergic receptor N-methyl-D-aspartate, in prefrontal cortex. We estimated an association between three polymorphisms of Fyn gene and performance on the Wisconsin Card Sorting Test, measuring prefrontal cortex functions, in 188 schizophrenic patients. Patients with T/T genotype of IVS10+T/C polymorphism and T/T genotype of Ex12+894T/G polymorphism made significantly less perseverative errors in the Wisconsin Card Sorting Test compared with patients with remaining genotypes, and obtained numerically better results in other Wisconsin Card Sorting Test domains. No significant differences in Wisconsin Card Sorting Test performance were found as to -93 A/G polymorphism. The main finding of the study is showing a relationship between polymorphisms of the Fyn gene, related to the function of glutamatergic system, and a performance on neuropsychological test of prefrontal cortex activity in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Psychiatr. Genet. 2007 Jun 17: 201-4 |
| PMID | 17417065 |
| Title | Polymorphisms of the Fyn kinase gene and a performance on the Wisconsin Card Sorting Test in schizophrenia. |
| Abstract | The glutamatergic system has been implicated in the pathogenesis and prefrontal cortex dysfunctions in schizophrenia. The SRC-family tyrosine kinase Fyn plays a key role in the interaction between brain-derived neurotrophic factor and glutamatergic receptor N-methyl-D-aspartate, in prefrontal cortex. We estimated an association between three polymorphisms of Fyn gene and performance on the Wisconsin Card Sorting Test, measuring prefrontal cortex functions, in 188 schizophrenic patients. Patients with T/T genotype of IVS10+T/C polymorphism and T/T genotype of Ex12+894T/G polymorphism made significantly less perseverative errors in the Wisconsin Card Sorting Test compared with patients with remaining genotypes, and obtained numerically better results in other Wisconsin Card Sorting Test domains. No significant differences in Wisconsin Card Sorting Test performance were found as to -93 A/G polymorphism. The main finding of the study is showing a relationship between polymorphisms of the Fyn gene, related to the function of glutamatergic system, and a performance on neuropsychological test of prefrontal cortex activity in schizophrenic patients. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Int. J. Cancer 2008 Aug 123: 511-8 |
| PMID | 18470912 |
| Title | Reduced tumor growth in a mouse model of schizophrenia, lacking the dopamine transporter. |
| Abstract | The incidence of cancer in patients with schizophrenia has been reported to be lower that in the general population. On the other hand, it is well established that patients with schizophrenia have a hyper-dopaminergic system and dopamine has the ability to inhibit tumor angiogenesis. Therefore, in order to investigate the molecular mechanisms responsible for the lower cancer risk in schizophrenic patients, we used a mouse model of schizophrenia, which shows hyper-dopaminergic transmission in the nerve terminals of dopaminergic neurons. Here, we hypothesized that tumor growth was reduced in a mouse model of schizophrenia, lacking the dopamine transporter (DAT), and investigated tumor growth and angiogenesis in DAT knockout mice. The subcutaneous tumor in mice inoculated with cancer cells was smaller in DAT-/- mice than in the wild type (p < 0.05); however, the level of plasma dopamine in DAT-/- mice was lower than that of control littermates. Using human umbilical vascular endothelial cells (HUVEC), we examined dopamine signaling through dopamine D(1) receptor (D(1)R) and D(2)R. Dopamine stimulation slightly decreased the surface expression of vascular endothelial growth factor receptor-2 (VEGF-R2) but induced the phosphorylation of VEGF-R2 through SRC in HUVEC. In addition, DAT-/- mice had less D(1)R. Both pharmacological and genetic interruption of D(1)R showed inhibited tumor growth. These results suggest that modulation of the dopaminergic system may contribute to cancer therapy. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | Int. J. Cancer 2008 Aug 123: 511-8 |
| PMID | 18470912 |
| Title | Reduced tumor growth in a mouse model of schizophrenia, lacking the dopamine transporter. |
| Abstract | The incidence of cancer in patients with schizophrenia has been reported to be lower that in the general population. On the other hand, it is well established that patients with schizophrenia have a hyper-dopaminergic system and dopamine has the ability to inhibit tumor angiogenesis. Therefore, in order to investigate the molecular mechanisms responsible for the lower cancer risk in schizophrenic patients, we used a mouse model of schizophrenia, which shows hyper-dopaminergic transmission in the nerve terminals of dopaminergic neurons. Here, we hypothesized that tumor growth was reduced in a mouse model of schizophrenia, lacking the dopamine transporter (DAT), and investigated tumor growth and angiogenesis in DAT knockout mice. The subcutaneous tumor in mice inoculated with cancer cells was smaller in DAT-/- mice than in the wild type (p < 0.05); however, the level of plasma dopamine in DAT-/- mice was lower than that of control littermates. Using human umbilical vascular endothelial cells (HUVEC), we examined dopamine signaling through dopamine D(1) receptor (D(1)R) and D(2)R. Dopamine stimulation slightly decreased the surface expression of vascular endothelial growth factor receptor-2 (VEGF-R2) but induced the phosphorylation of VEGF-R2 through SRC in HUVEC. In addition, DAT-/- mice had less D(1)R. Both pharmacological and genetic interruption of D(1)R showed inhibited tumor growth. These results suggest that modulation of the dopaminergic system may contribute to cancer therapy. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | J. Biol. Chem. 2008 Jun 283: 17194-204 |
| PMID | 18442977 |
| Title | Activation of 5-HT2A/C receptors counteracts 5-HT1A regulation of n-methyl-D-aspartate receptor channels in pyramidal neurons of prefrontal cortex. |
| Abstract | Abnormal serotonin-glutamate interaction in prefrontal cortex (PFC) is implicated in the pathophysiology of many mental disorders, including schizophrenia and depression. However, the mechanisms by which this interaction occurs remain unclear. Our previous study has shown that activation of 5-HT(1A) receptors inhibits N-methyl-D-aspartate (NMDA) receptor (NMDAR) currents in PFC pyramidal neurons by disrupting microtubule-based transport of NMDARs. Here we found that activation of 5-HT(2A/C) receptors significantly attenuated the effect of 5-HT(1A) on NMDAR currents and microtubule depolymerization. The counteractive effect of 5-HT(2A/C) on 5-HT(1A) regulation of synaptic NMDAR response was also observed in PFC pyramidal neurons from intact animals treated with various 5-HT-related drugs. Moreover, 5-HT(2A/C) stimulation triggered the activation of extracellular signal-regulated kinase (ERK) in dendritic processes. Inhibition of the beta-arrestin/SRC/dynamin signaling blocked 5-HT(2A/C) activation of ERK and the counteractive effect of 5-HT(2A/C) on 5-HT(1A) regulation of NMDAR currents. Immunocytochemical studies showed that 5-HT(2A/C) treatment blocked the inhibitory effect of 5-HT(1A) on surface NR2B clusters on dendrites, which was prevented by cellular knockdown of beta-arrestins. Taken together, our study suggests that serotonin, via 5-HT(1A) and 5-HT(2A/C) receptor activation, regulates NMDAR functions in PFC neurons in a counteractive manner. 5-HT(2A/C), by activating ERK via the beta-arrestin-dependent pathway, opposes the 5-HT(1A) disruption of microtubule stability and NMDAR transport. These findings provide a framework for understanding the complex interactions between serotonin and NMDARs in PFC, which could be important for cognitive and emotional control in which both systems are highly involved. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | Psychiatry Res 2009 Jul 168: 119-28 |
| PMID | 19501919 |
| Title | Decreased expression of Fyn protein and disbalanced alternative splicing patterns in platelets from patients with schizophrenia. |
| Abstract | Fyn, a SRC-family kinase, is highly expressed in brain tissue and blood cells. In the mouse brain, Fyn participates in brain development, synaptic transmission through the phosphorylation of N-methyl-d-aspartate (NMDA) receptor subunits, and the regulation of emotional behavior. Recently, we found that Fyn is required for the signal transduction in striatal neurons that is initiated by haloperidol, an antipsychotic drug. To determine whether Fyn abnormalities are present in patients with schizophrenia, we analyzed Fyn expression in platelet samples from 110 patients with schizophrenia, 75 of the patients' first-degree relatives, and 130 control subjects. A Western blot analysis revealed significantly lower levels of Fyn protein among the patients with schizophrenia and their relatives, compared with the level in the control group. At the mRNA level, the splicing patterns of fyn were altered in the patients and their relatives; specifically, the ratio of fynDelta7, in which exon 7 is absent, was elevated. An expression study in HEK293T cells revealed that FynDelta7 had a dominant-negative effect on the phosphorylation of Fyn's substrate. These results suggest novel deficits in Fyn function, manifested as the downregulation of Fyn protein or the altered transcription of the fyn gene, in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | Neuropsychobiology 2009 -1 59: 178-83 |
| PMID | 19468241 |
| Title | FYN kinase gene: another glutamatergic gene associated with bipolar disorder? |
| Abstract | Several genes of the glutamatergic system have been implicated in both schizophrenia and bipolar disorder. The SRC family tyrosine kinase FYN plays a key role in the interaction between brain-derived neurotrophic factor and glutamatergic receptor N-methyl-D-aspartate. Although no association between FYN gene polymorphisms and schizophrenia has been demonstrated, in our previous paper we found an association between FYN polymorphisms and cognitive test performance in schizophrenic patients. The aim of this study was to find a possible association of three polymorphisms of the FYN gene with bipolar disorder. We analyzed 425 bipolar patients and 518 control subjects. Genotypes of three analyzed polymorphisms, i.e. rs706895 (-93A/G in the 5'-flanking region), rs6916861 (Ex12+894T/G in the 3'-UTR) and rs3730353 (IVS10+37T/C in intron 10) were established by PCR-RFLP. A significant association was found between rs6916861 T/G and rs3730353 T/C polymorphisms of the FYN gene and bipolar disorder. These results were also significant in the subgroups of bipolar I and early-onset (<18 years) bipolar disorder patients. No association with -93 A/G polymorphism was found. Haplotype analysis revealed that rs6916861 T/G and rs3730353 T/C polymorphisms are in linkage disequilibrium (r(2) = 0.86, D' = 0.93 with 95% CI = 0.9-0.97). The results suggest that the glutamatergic FYN gene may be associated with bipolar disorder, particularly with type I illness and early age of onset. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 11 | Neuropsychobiology 2009 -1 59: 178-83 |
| PMID | 19468241 |
| Title | FYN kinase gene: another glutamatergic gene associated with bipolar disorder? |
| Abstract | Several genes of the glutamatergic system have been implicated in both schizophrenia and bipolar disorder. The SRC family tyrosine kinase FYN plays a key role in the interaction between brain-derived neurotrophic factor and glutamatergic receptor N-methyl-D-aspartate. Although no association between FYN gene polymorphisms and schizophrenia has been demonstrated, in our previous paper we found an association between FYN polymorphisms and cognitive test performance in schizophrenic patients. The aim of this study was to find a possible association of three polymorphisms of the FYN gene with bipolar disorder. We analyzed 425 bipolar patients and 518 control subjects. Genotypes of three analyzed polymorphisms, i.e. rs706895 (-93A/G in the 5'-flanking region), rs6916861 (Ex12+894T/G in the 3'-UTR) and rs3730353 (IVS10+37T/C in intron 10) were established by PCR-RFLP. A significant association was found between rs6916861 T/G and rs3730353 T/C polymorphisms of the FYN gene and bipolar disorder. These results were also significant in the subgroups of bipolar I and early-onset (<18 years) bipolar disorder patients. No association with -93 A/G polymorphism was found. Haplotype analysis revealed that rs6916861 T/G and rs3730353 T/C polymorphisms are in linkage disequilibrium (r(2) = 0.86, D' = 0.93 with 95% CI = 0.9-0.97). The results suggest that the glutamatergic FYN gene may be associated with bipolar disorder, particularly with type I illness and early age of onset. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 12 | J. Neurochem. 2009 May 109: 1017-30 |
| PMID | 19519774 |
| Title | Activation of dopamine D1 receptors blocks phencyclidine-induced neurotoxicity by enhancing N-methyl-D-aspartate receptor-mediated synaptic strength. |
| Abstract | Early postnatal blockade of NMDA receptors by phencyclidine (PCP) causes cortical apoptosis in animals. This is associated with the development of schizophrenia-like behaviors in rats later in life. Recent studies show that the mechanism involves a loss of neurotrophic support from the phosphoinositol-3 kinase/Akt pathway, which is normally maintained by synaptic NMDA receptor activation. Here we report that activation of dopamine D1 receptors (D1R) with dihydrexidine (DHX) prevents PCP-induced neurotoxicity in cortical neurons by enhancing the efficacy of NMDAergic synapses. DHX increases serine phosphorylation of the NR1 subunit through protein kinase A activation and tyrosine phosphorylation of the NR2B subunit via SRC kinase. DHX enhances recruitment of NR1 and NR2B, but not NR2A, into synapses. DHX also facilitated the synaptic response in cortical slices and this was blocked by an NR2B antagonist. DHX pre-treatment of rat pups prior to PCP on postnatal days 7, 9 and 11 inhibited PCP-induced caspase-3 activation on PN11 and deficits in pre-pulse inhibition of acoustic startle measured on PN 26-28. In summary, these data demonstrate that PCP-induced deficits in NMDA receptor function, neurotoxicity and subsequent behavioral deficits may be prevented by D1R activation in the cortex and further, it is suggested that D1R activation may be beneficial in treating schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 13 | Mol Brain 2010 -1 3: 20 |
| PMID | 20569495 |
| Title | Dopamine D1 receptor-mediated NMDA receptor insertion depends on Fyn but not Src kinase pathway in prefrontal cortical neurons. |
| Abstract | Interactions between dopamine and glutamate in the prefrontal cortex are essential for cognitive functions such as working memory. Modulation of N-methyl-D-aspartic acid (NMDA) receptor functions by dopamine D1 receptor is believed to play a critical role in these functions. The aim of the work reported here is to explore the signaling pathway underlying D1 receptor-mediated trafficking of NMDA receptors in cultured rat prefrontal cortical neurons. Activation of D1 receptor by selective agonist SKF-81297 significantly increased the expression of NR2B subunits. This effect was completely blocked by small interfering RNA knockdown of Fyn, but not SRC. Under control conditions, neither Fyn nor SRC knockdown exhibited significant effect on basal NR2B expression. D1 stimulation significantly enhanced NR2B insertion into plasma membrane in cultured PFC neurons, a process obstructed by Fyn, but not SRC, knockdown. Dopamine D1 receptor-mediated increase of NMDA receptors is thus Fyn kinase dependent. Targeting this signaling pathway may be useful in treating drug addiction and schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 14 | J. Neurosci. 2010 Oct 30: 13513-24 |
| PMID | 20926677 |
| Title | Serotonin, but not N-methyltryptamines, activates the serotonin 2A receptor via a ß-arrestin2/Src/Akt signaling complex in vivo. |
| Abstract | Hallucinogens mediate many of their psychoactive effects by activating serotonin 2A receptors (5-HT(2A)R). Although serotonin is the cognate endogenous neurotransmitter and is not considered hallucinogenic, metabolites of serotonin also have high affinity at 5-HT(2A)R and can induce hallucinations in humans. Here we report that serotonin differs from the psychoactive N-methyltryptamines by its ability to engage a ?-arrestin2-mediated signaling cascade in the frontal cortex. Serotonin and 5-hydroxy-L-tryptophan (5-HTP) induce a head-twitch response in wild-type (WT) mice that is a behavioral proxy for 5-HT(2A)R activation. The response in ?-arrestin2 knock-out (?arr2-KO) mice is greatly attenuated until the doses are elevated, at which point, ?arr2-KO mice display a head-twitch response that can exceed that of WT mice. Direct administration of N-methyltryptamines also produces a greater response in ?arr2-KO mice. Moreover, the inhibition of N-methyltransferase blocks 5-HTP-induced head twitches in ?arr2-KO mice, indicating that N-methyltryptamines, rather than serotonin, primarily mediate this response. Biochemical studies demonstrate that serotonin stimulates Akt phosphorylation in the frontal cortex and in primary cortical neurons through the activation of a ?-arrestin2/phosphoinositide 3-kinase/SRC/Akt cascade, whereas N-methyltryptamines do not. Furthermore, disruption of any of the components of this cascade prevents 5-HTP-induced, but not N-methyltryptamine-induced, head twitches. We propose that there is a bifurcation of 5-HT(2A)R signaling that is neurotransmitter and ?-arrestin2 dependent. This demonstration of agonist-directed 5-HT(2A)R signaling in vivo may significantly impact drug discovery efforts for the treatment of disorders wherein hallucinations are part of the etiology, such as schizophrenia, or manifest as side effects of treatment, such as depression. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 15 | J. Neurochem. 2010 Jul 114: 62-73 |
| PMID | 20374423 |
| Title | Dopamine D(1) receptor-mediated enhancement of NMDA receptor trafficking requires rapid PKC-dependent synaptic insertion in the prefrontal neurons. |
| Abstract | Understanding the interaction between dopamine and glutamate, particularly the interaction of dopamine and NMDA receptors, may enable a more rational approach to the treatment of schizophrenia, drug addiction, and other psychiatric disorders. We show that, in prefrontal cortical neurons, dopamine D(1)-induced enhancement of NMDA receptor function depends on rapid insertion of new NMDA receptor 2B subunits on the synaptic surface. Protein kinase A (PKA) inhibitor, but not protein kinase C (PKC) inhibitor, completely blocked dopamine D(1) agonist SKF-81297-induced increase of the total expression of NMDA receptors. Furthermore, SKF-81297 failed to alter the surface expression and synaptic insertion of NMDA receptors in the presence of PKA inhibitor, phospholipase C inhibitor, PKC inhibitor, or SRC family kinase inhibitor. Our data suggest that D(1)-mediated enhancement of NMDA current depends on the NMDA receptor trafficking through rapid synaptic insertion and both PKA and PKC signaling pathways play important roles in the regulatory process. Although both PKA and PKC mediate the D(1)-induced enhancement of NMDA receptors, the phospholipase C-PKC-SRC pathway is only required for surface expression and new synaptic insertion of NMDA receptors. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 16 | Nat. Med. 2011 Apr 17: 425-7 |
| PMID | 21475235 |
| Title | A Src link in schizophrenia. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic |
| 17 | Nat. Med. 2011 Apr 17: 470-8 |
| PMID | 21441918 |
| Title | Schizophrenia susceptibility pathway neuregulin 1-ErbB4 suppresses Src upregulation of NMDA receptors. |
| Abstract | Hypofunction of the N-methyl D-aspartate subtype of glutamate receptor (NMDAR) is hypothesized to be a mechanism underlying cognitive dysfunction in individuals with schizophrenia. For the schizophrenia-linked genes NRG1 and ERBB4, NMDAR hypofunction is thus considered a key detrimental consequence of the excessive NRG1-ErbB4 signaling found in people with schizophrenia. However, we show here that neuregulin 1?-ErbB4 (NRG1?-ErbB4) signaling does not cause general hypofunction of NMDARs. Rather, we find that, in the hippocampus and prefrontal cortex, NRG1?-ErbB4 signaling suppresses the enhancement of synaptic NMDAR currents by the nonreceptor tyrosine kinase SRC. NRG1?-ErbB4 signaling prevented induction of long-term potentiation at hippocampal Schaffer collateral-CA1 synapses and suppressed SRC-dependent enhancement of NMDAR responses during theta-burst stimulation. Moreover, NRG1?-ErbB4 signaling prevented theta burst-induced phosphorylation of GluN2B by inhibiting SRC kinase activity. We propose that NRG1-ErbB4 signaling participates in cognitive dysfunction in schizophrenia by aberrantly suppressing SRC-mediated enhancement of synaptic NMDAR function. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 18 | Behav. Brain Res. 2011 Sep 223: 24-9 |
| PMID | 21515312 |
| Title | Executive control in chronic schizophrenia: A perspective from manual stimulus-response compatibility task performance. |
| Abstract | Antisaccade deficits are a well-documented pathophysiological characteristic in schizophrenia. However, it is yet unclear whether these findings reflect a specific oculomotor deficit, general psychomotor impairment or disturbance in executive control mechanisms. Performance in a manual stimulus-response compatibility (SRC) task and a neuropsychological test-battery covering different cognitive and motor domains were obtained in 28 patients with chronic schizophrenia. It was compared with a normative cohort of healthy subjects and validated by comparison with a sub-sample of that cohort consisting of 28 age, gender and education matched controls. Patients showed significantly worse performance than controls in tests requiring maintenance or manipulating of multiple components but were unimpaired in simple motor, memory or executive tasks. In the SRC task patients had a significantly worse performance in the congruent condition and also a significantly higher increase in error rate from the congruent to the incongruent condition. There were, however, neither a group difference nor a group-by-condition interaction with respect to reaction times. : Our results provide evidence against an isolated oculomotor deficit but also against an undifferentiated psychomotor dysfunction in chronic schizophrenia. Rather, in synopsis with previous reports on antisaccade performance, it becomes evident that the degree of impairment follows closely the amount of executive control required in a task, which in turn may relate to dysfunctional top-down bias of the prefrontal cortex arising from unstable task instructions. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 19 | Bull. Math. Biol. 2012 Mar 74: 717-35 |
| PMID | 22147103 |
| Title | A model of neuregulin control of NMDA receptors on synaptic spines. |
| Abstract | Neuregulin (Nrg) through its receptor ErbB4 modulates the activity of the N-Methyl-D-Aspartate (NMDA) receptor (NMDAR) at synapses. As modification of this pathway has been implicated in schizophrenia, it is of great interest to define it in precise quantitative terms. Kinetic models of the epidermal growth factor (EGF)/ErbB receptor signalling pathway describing activation, desensitization, and tyrosine phosphorylation of EGFR/ErbB followed by binding and activation of SRC family kinases that is subsequently followed by phosphorylation of target proteins are available. We have adapted these to give a kinetic description of NMDAR modulation by Nrg that recapitulates the observed kinetics of autophosphorylation of the ErbB dimer as well as the modulation of the NMDAR by SRC kinase, according to whether the kinases are activated or deactivated. This quantitative description of the Nrg/NMDAR pathway provides a model for experimental elucidation of what goes awry in animal models of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 20 | FEBS J. 2012 Jan 279: 2-11 |
| PMID | 21985289 |
| Title | Dysregulated Src upregulation of NMDA receptor activity: a common link in chronic pain and schizophrenia. |
| Abstract | Upregulation of N-methyl-D-aspartate (NMDA) receptor function by the nonreceptor protein tyrosine kinase SRC has been implicated in physiological plasticity at glutamatergic synapses. Here, we highlight recent findings suggesting that aberrant SRC upregulation of NMDA receptors may also be key in pathophysiological conditions. Within the nociceptive processing network in the dorsal horn of the spinal cord, pathologically increased SRC upregulation of NMDA receptors is critical for pain hypersensitivity in models of chronic inflammatory and neuropathic pain. On the other hand, in the hippocampus and prefrontal cortex, the physiological upregulation of NMDA receptors by SRC is blocked by neuregulin 1-ErbB4 signaling, a pathway that is genetically implicated in the positive symptoms of schizophrenia. Thus, either over-upregulation or under-upregulation of NMDA receptors by SRC may lead to pathological conditions in the central nervous system. Therefore, normalizing SRC upregulation of NMDA receptors may be a novel therapeutic approach for central nervous system disorders, without the deleterious consequences of directly blocking NMDA receptors. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 21 | Pharmacol. Rev. 2012 Jan 64: 65-87 |
| PMID | 22090472 |
| Title | Therapeutic implications for striatal-enriched protein tyrosine phosphatase (STEP) in neuropsychiatric disorders. |
| Abstract | Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific phosphatase that modulates key signaling molecules involved in synaptic plasticity and neuronal function. Targets include extracellular-regulated kinase 1 and 2 (ERK1/2), stress-activated protein kinase p38 (p38), the SRC family tyrosine kinase Fyn, N-methyl-D-aspartate receptors (NMDARs), and ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). STEP-mediated dephosphorylation of ERK1/2, p38, and Fyn leads to inactivation of these enzymes, whereas STEP-mediated dephosphorylation of surface NMDARs and AMPARs promotes their endocytosis. Accordingly, the current model of STEP function posits that it opposes long-term potentiation and promotes long-term depression. Phosphorylation, cleavage, dimerization, ubiquitination, and local translation all converge to maintain an appropriate balance of STEP in the central nervous system. Accumulating evidence over the past decade indicates that STEP dysregulation contributes to the pathophysiology of several neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, fragile X syndrome, epileptogenesis, alcohol-induced memory loss, Huntington's disease, drug abuse, stroke/ischemia, and inflammatory pain. This comprehensive review discusses STEP expression and regulation and highlights how disrupted STEP function contributes to the pathophysiology of diverse neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 22 | 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 |
| 23 | Mol. Cell. Neurosci. 2013 Sep 56: 128-39 |
| PMID | 23628905 |
| Title | Predicting protein-protein interactions in the post synaptic density. |
| Abstract | The post synaptic density (PSD) is a specialization of the cytoskeleton at the synaptic junction, composed of hundreds of different proteins. Characterizing the protein components of the PSD and their interactions can help elucidate the mechanism of long-term changes in synaptic plasticity, which underlie learning and memory. Unfortunately, our knowledge of the proteome and interactome of the PSD is still partial and noisy. In this study we describe a computational framework to improve the reconstruction of the PSD network. The approach is based on learning the characteristics of PSD protein interactions from a set of trusted interactions, expanding this set with data collected from large scale repositories, and then predicting novel interaction with proteins that are suspected to reside in the PSD. Using this method we obtained thirty predicted interactions, with more than half of which having supporting evidence in the literature. We discuss in details two of these new interactions, Lrrtm1 with PSD-95 and SRC with Capg. The first may take part in a mechanism underlying glutamatergic dysfunction in schizophrenia. The second suggests an alternative mechanism to regulate dendritic spines maturation. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 24 | Schizophr Res Treatment 2013 -1 2013: 531938 |
| PMID | 24386567 |
| Title | Grasping the world: object-affordance effect in schizophrenia. |
| Abstract | For schizophrenic patients, the world can appear as deprived of practical meaning, which normally emerges from sensory-motor experiences. However, no research has yet studied the integration between perception and action in this population. In this study, we hypothesize that patients, after having controlled the integrity of their visuospatial integration, would nevertheless present deficit in sensory-motor simulation. In this view, we compare patients to control subjects using two stimulus-response compatibility (SRC) tasks. Experiment 1 is performed to ensure that visuo-spatial integration is not impaired (Simon Effect). Experiment 2 replicates a study from Tucker and Ellis (1998) to explore the existence of sensory-motor compatibility between stimulus and response (Object Affordance). In control subjects, the SRC effect appears in both experiments. In schizophrenic patients, it appears only when stimuli and responses share the same spatial localization. This loss of automatic sensory-motor simulation could emerge from a lack of relation between the object and the subject's environment. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 25 | Schizophr Res Treatment 2013 -1 2013: 531938 |
| PMID | 24386567 |
| Title | Grasping the world: object-affordance effect in schizophrenia. |
| Abstract | For schizophrenic patients, the world can appear as deprived of practical meaning, which normally emerges from sensory-motor experiences. However, no research has yet studied the integration between perception and action in this population. In this study, we hypothesize that patients, after having controlled the integrity of their visuospatial integration, would nevertheless present deficit in sensory-motor simulation. In this view, we compare patients to control subjects using two stimulus-response compatibility (SRC) tasks. Experiment 1 is performed to ensure that visuo-spatial integration is not impaired (Simon Effect). Experiment 2 replicates a study from Tucker and Ellis (1998) to explore the existence of sensory-motor compatibility between stimulus and response (Object Affordance). In control subjects, the SRC effect appears in both experiments. In schizophrenic patients, it appears only when stimuli and responses share the same spatial localization. This loss of automatic sensory-motor simulation could emerge from a lack of relation between the object and the subject's environment. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 26 | PLoS ONE 2014 -1 9: e90425 |
| PMID | 24632812 |
| Title | Transcriptomic analysis of the effects of a fish oil enriched diet on murine brains. |
| Abstract | The health benefits of fish oil enriched with high omega-3 polyunsaturated fatty acids (n-3 PUFA) are widely documented. Fish oil as dietary supplements, however, show moderate clinical efficacy, highlighting an immediate scope of systematic in vitro feedback. Our transcriptomic study was designed to investigate the genomic shift of murine brains fed on fish oil enriched diets. A customized fish oil enriched diet (FD) and standard lab diet (SD) were separately administered to two randomly chosen populations of C57BL/6J mice from their weaning age until late adolescence. Statistical analysis mined 1,142 genes of interest (GOI) differentially altered in the hemibrains collected from the FD- and SD-fed mice at the age of five months. The majority of identified GOI (? 40%) encodes proteins located in the plasma membrane, suggesting that fish oil primarily facilitated the membrane-oriented biofunctions. FD potentially augmented the nervous system's development and functions by selectively stimulating the SRC-mediated calcium-induced growth cascade and the downstream PI3K-AKT-PKC pathways. FD reduced the amyloidal burden, attenuated oxidative stress, and assisted in somatostatin activation-the signatures of attenuation of Alzheimer's disease, Parkinson's disease, and affective disorder. FD induced elevation of FKBP5 and suppression of BDNF, which are often linked with the improvement of anxiety disorder, depression, and post-traumatic stress disorder. Hence we anticipate efficacy of FD in treating illnesses such as depression that are typically triggered by the hypoactivities of dopaminergic, adrenergic, cholinergic, and GABAergic networks. Contrastingly, FD's efficacy could be compromised in treating illnesses such as bipolar disorder and schizophrenia, which are triggered by hyperactivities of the same set of neuromodulators. A more comprehensive investigation is recommended to elucidate the implications of fish oil on disease pathomechanisms, and the result-driven repositioning of fish oil utilization may revitalize its therapeutic efficacy. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 27 | J Neural Transm (Vienna) 2014 May 121: 479-90 |
| PMID | 24380930 |
| Title | Global signaling effects of a schizophrenia-associated missense mutation in neuregulin 1: an exploratory study using whole genome and novel kinome approaches. |
| Abstract | Aberrant neuregulin 1-ErbB4 signaling has been implicated in schizophrenia. We previously identified a novel schizophrenia-associated missense mutation (valine to leucine) in the NRG1 transmembrane domain. This variant inhibits formation of the NRG1 intracellular domain (ICD) and causes decreases in dendrite formation. To assess the global effects of this mutation, we used lymphoblastoid cell lines from unaffected heterozygous carriers (Val/Leu) and non-carriers (Val/Val). Transcriptome data showed 367 genes differentially expressed between the two groups (Val/Val N = 6, Val/Leu N = 5, T test, FDR (1 %), ? = 0.05, -log10 p value >1.5). Ingenuity pathway (IPA) analyses showed inflammation and NRG1 signaling as the top pathways altered. Within NRG1 signaling, protein kinase C (PKC)-eta (PRKCH) and non-receptor tyrosine kinase (SRC) were down-regulated in heterozygous carriers. Novel kinome profiling (serine/threonine) was performed after stimulating cells (V/V N = 6, V/L N = 6) with ErbB4, to induce release of the NRG1 ICD, and revealed significant effects of treatment on the phosphorylation of 35 peptides. IPA showed neurite outgrowth (six peptides) as the top annotated function. Phosphorylation of these peptides was significantly decreased in ErbB4-treated Val/Val but not in Val/Leu cells. These results show that perturbing NRG1 ICD formation has major effects on cell signaling, including inflammatory and neurite formation pathways, and may contribute significantly to schizophrenia pathophysiology. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 28 | Front Cell Neurosci 2014 Jan 7: 284 |
| PMID | 24431989 |
| Title | Axon-glia interaction and membrane traffic in myelin formation. |
| Abstract | In vertebrate nervous systems myelination of neuronal axons has evolved to increase conduction velocity of electrical impulses with minimal space and energy requirements. Myelin is formed by specialized glial cells which ensheath axons with a lipid-rich insulating membrane. Myelination is a multi-step process initiated by axon-glia recognition triggering glial polarization followed by targeted myelin membrane expansion and compaction. Thereby, a myelin sheath of complex subdomain structure is established. Continuous communication between neurons and glial cells is essential for myelin maintenance and axonal integrity. A diverse group of diseases, from multiple sclerosis to schizophrenia, have been linked to malfunction of myelinating cells reflecting the physiological importance of the axon-glial unit. This review describes the mechanisms of axonal signal integration by oligodendrocytes emphasizing the central role of the SRC-family kinase Fyn during central nervous system (CNS) myelination. Furthermore, we discuss myelin membrane trafficking with particular focus on endocytic recycling and the control of proteolipid protein (PLP) transport by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. Finally, PLP mistrafficking is considered in the context of myelin diseases. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 29 | Front Cell Neurosci 2014 -1 8: 132 |
| PMID | 24904279 |
| Title | The sodium leak channel, NALCN, in health and disease. |
| Abstract | Ion channels are crucial components of cellular excitability and are involved in many neurological diseases. This review focuses on the sodium leak, G protein-coupled receptors (GPCRs)-activated NALCN channel that is predominantly expressed in neurons where it regulates the resting membrane potential and neuronal excitability. NALCN is part of a complex that includes not only GPCRs, but also UNC-79, UNC-80, NLF-1 and SRC family of Tyrosine kinases (SFKs). There is growing evidence that the NALCN channelosome critically regulates its ion conduction. Both in mammals and invertebrates, animal models revealed an involvement in many processes such as locomotor behaviors, sensitivity to volatile anesthetics, and respiratory rhythms. There is also evidence that alteration in this NALCN channelosome can cause a wide variety of diseases. Indeed, mutations in the NALCN gene were identified in Infantile Neuroaxonal Dystrophy (INAD) patients, as well as in patients with an Autosomal Recessive Syndrome with severe hypotonia, speech impairment, and cognitive delay. Deletions in NALCN gene were also reported in diseases such as 13q syndrome. In addition, genes encoding NALCN, NLF- 1, UNC-79, and UNC-80 proteins may be susceptibility loci for several diseases including bipolar disorder, schizophrenia, Alzheimer's disease, autism, epilepsy, alcoholism, cardiac diseases and cancer. Although the physiological role of the NALCN channelosome is poorly understood, its involvement in human diseases should foster interest for drug development in the near future. Toward this goal, we review here the current knowledge on the NALCN channelosome in physiology and diseases. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 30 | Mol. Psychiatry 2015 Sep 20: 1091-100 |
| PMID | 25330739 |
| Title | Src kinase as a mediator of convergent molecular abnormalities leading to NMDAR hypoactivity in schizophrenia. |
| Abstract | Numerous investigations support decreased glutamatergic signaling as a pathogenic mechanism of schizophrenia, yet the molecular underpinnings for such dysregulation are largely unknown. In the post-mortem dorsolateral prefrontal cortex (DLPFC), we found striking decreases in tyrosine phosphorylation of N-methyl-D aspartate (NMDA) receptor subunit 2 (GluN2) that is critical for neuroplasticity. The decreased GluN2 activity in schizophrenia may not be because of downregulation of NMDA receptors as MK-801 binding and NMDA receptor complexes in postsynaptic density (PSD) were in fact increased in schizophrenia cases. At the postreceptor level, however, we found striking reductions in the protein kinase C, Pyk 2 and SRC kinase activity that in tandem can decrease GluN2 activation. Given that SRC serves as a hub of various signaling mechanisms affecting GluN2 phosphorylation, we postulated that SRC hypoactivity may result from convergent alterations of various schizophrenia susceptibility pathways and thus mediate their effects on NMDA receptor signaling. Indeed, the DLPFC of schizophrenia cases exhibit increased PSD-95 and erbB4 and decreased receptor-type tyrosine-protein phosphatase-? (RPTP?) and dysbindin-1, each of which reduces SRC activity via protein interaction with SRC. To test genomic underpinnings for SRC hypoactivity, we examined genome-wide association study results, incorporating 13?394 cases and 34?676 controls. We found no significant association of individual variants of SRC and its direct regulators with schizophrenia. However, a protein-protein interaction-based network centered on SRC showed significant enrichment of gene-level associations with schizophrenia compared with other psychiatric illnesses. Our results together demonstrate striking decreases in NMDA receptor signaling at the postreceptor level and propose SRC as a nodal point of convergent dysregulations affecting NMDA receptor pathway via protein-protein associations. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 31 | J. Neurosci. Res. 2015 Feb 93: 215-29 |
| PMID | 25242528 |
| Title | Tyrosine 251 at the C-terminus of neuronal glycoprotein M6a is critical for neurite outgrowth. |
| Abstract | Neuronal glycoprotein M6a is involved in neuronal plasticity, promoting neurite and filopodia outgrowth and, likely, synaptogenesis. Polymorphisms in the human M6a gene GPM6A have recently been associated with mental illnesses such as schizophrenia, bipolar disorders, and claustrophobia. Nevertheless, the molecular bases underlying these observations remain unknown. We have previously documented that, to induce filopodia formation, M6a depends on the association of membrane lipid microdomains and the activation of SRC and mitogen-activated protein kinase kinases. Here, in silico analysis of the phosphorylation of tyrosine 251 (Y251) at the C-terminus of M6a showed that it could be a target of SRC kinases. We examined whether phosphorylation of M6a at Y251 affects neurite and filopodia outgrowth and the targets involved in its signal propagation. This work provides evidence that the SRC kinase family and the phosphatidylinositide 3-kinase (PI3K), but not Ras, participate in M6a signal cascade leading to neurite/filopodia outgrowth in hippocampal neurons and murine neuroblastoma N2a cells. Phosphorylation of M6a at Y251 is essential only for neurite outgrowth by the PI3K/AKT-mediated pathway and, moreover, rescues the inhibition caused by selective SRC inhibitor and external M6a monoclonal antibody treatment. Thus, we suggest that phosphorylation of M6a at Y251 is critical for a specific stage of neuronal development and triggers redundant signaling pathways leading to neurite extension. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 32 | J Neural Transm (Vienna) 2015 Mar 122: 477-85 |
| PMID | 25005592 |
| Title | Sequencing and expression analyses of the synaptic lipid raft adapter gene PAG1 in schizophrenia. |
| Abstract | Disruption of synaptic networks has been advocated in the pathogenesis of psychiatric diseases like schizophrenia. The majority of synaptic proteins involved in neuronal communications are localized in lipid rafts. These rafts form the platform for coordinating neuronal signal transduction, by clustering interacting partners. The PAG1 protein is a transmembrane adaptor protein in the lipid raft signaling cluster that regulates SRC family kinases (SFKs), a convergent point for multiple pathways regulating N-methyl-D-aspartate (NMDA) receptors. Reports of de novo missense mutations in PAG1 and SFK mediated reductions in tyrosine phosphorylation of NMDA receptor subunit proteins in schizophrenia patients, point to a putative role in schizophrenia pathogenesis. To evaluate this, we resequenced the entire coding region of PAG1 in Japanese schizophrenia patients (n = 1,140) and controls (n = 1,140). We identified eight missense variants, of which four were previously unreported. Case-control genetic association analysis of these variants in a larger cohort (n = 4,182) showed neither a statistically significant association of the individual variants with schizophrenia, nor any increased burden of the rare alleles in the patient group. Expression levels of PAG1 in post-mortem brain samples from schizophrenia patients and controls also showed no significant differences. To assess the precise role of PAG1 in schizophrenia, future studies with larger sample sizes are needed. |
| SCZ Keywords | schizophrenia, schizophrenic |