| 1 | Neurochem. Res. 2000 Oct 25: 1207-18 |
|---|---|
| PMID | 11059795 |
| Title | New neurochemical markers for psychosis: a working hypothesis of their operation. |
| Abstract | Reelin (Reln) is expressed in specific GABAergic neurons in layer I and II of neocortex, and is secreted into the extracellular matrix where it surrounds dendrites, spines and neurite arborizations, and binds to integrin receptors located on post-synaptic densities of apical dendritic spines. Experiments in rodents (including wild type or reeler heterozygous mice) and non-human primates suggest the Reln secreted in the extracellular matrix of neocortex, via integrin receptors, modulates the function of the adaptor protein DAB1(drosophila disable-gene) homologous product) thereby participating in dynamic processes associated with plasticity changes in dendrites, dendritic spines and their synapses. A local protein synthesis at dendritic spines (ie the activity regulated cytoskeleton associated protein, ARC) probably acts as a signal for plastic modulatory activities in synapses operative in neural group interactions. A reseARCh strategy directed toward identifying specific neurochemical markers operative in the etiopathology of psychotic disorders lead to the identification of a downregulation (30-50%) of Reln and glutamic acid decarboxylase 67(GAD67) expression in prefrontal cortex and other brain areas of schizoprenia and bipolar disorder patients with psychosis. These downregulations were not due to neuronal damage, postmortem interval, or antipsychotic medication. The dysfunction of GABAergic interneurons observed in psychotic brains in combination with reduced Reln expression and downregulation of Reln-integrin receptor interaction, may provide an explanation for the reported decrease in neuropile expression including dendritic spine density reduction, in neocortex of schizophrenia patients. This downregulation of neuropile plasticity may be a factor to be considered in the etiology of the disintegration of consciousness, which is one of the primary signs of psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 2 | J. Neurobiol. 2003 Oct 57: 67-80 |
| PMID | 12973829 |
| Title | Aberrant neuronal connectivity in CHL1-deficient mice is associated with altered information processing-related immediate early gene expression. |
| Abstract | In humans, loss or alteration of the CHL1/CALL gene may contribute to mental impairment associated with the 3p-syndrome, caused by distal deletions of the short (p) arm of chromosome 3, and schizophrenia. Mice deficient for the Close Homologue of L1 (CHL1) show aberrant connectivity of hippocampal mossy fibers and olfactory sensory axons, suggesting participation of CHL1 in the establishment of neuronal networks. Furthermore, behavioral studies showed that CHL1-deficient mice react differently towards novel experimental environments. These data raise the hypothesis that processing of information, possibly novel versus familiar, may be altered in the absence of CHL1. To test this hypothesis, brain activities were investigated after presentation of a novel, familiar, or neutral gustatory stimulus using metabolic mapping with ((14)C)-2-deoxyglucose (2-DG) and analysis of mRNA expression of the immediate early genes (IEGs) c-fos and arg 3.1/ARC by in situ hybridization. 2-DG labeling revealed only small differences between CHL1-deficient and wild-type littermate mice. In contrast, while the specific novelty-induced increase in c-fos expression was maintained in most of the brain areas analyzed, c-fos mRNA expression was similar after the novel and familiar taste in several brain areas of the CHL1-deficient mice. Furthermore, in these mutants, arg 3.1/ARC expression was slightly reduced after the novel taste and increased after the familiar taste, leading to a similar arg 3.1/ARC mRNA expression after both stimuli. Our results indicate that, in contrast to controls, CHL1-deficient mice might process novel and familiar information similarly and suggest that the altered neuronal connectivity in these mutants disturbs information processing at the molecular level. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 3 | Hist Psychiatry 2003 Dec 14: 411-58 |
| PMID | 14740633 |
| Title | Karl Kleist (1879-1960)- a pioneer of neuropsychiatry. |
| Abstract | Karl Kleist (1879-1960) was instrumental in pioneering German neuropsychiatry and neuropsychology, including the description of frontal, constructional, limb-kinetic (innervatory) and psychomotor apraxias, frontal akinesia and aspontaneity, as well as object and form blindness. Besides isolating episodic twilight states, involutional paranoia and symptomatic (especially influenza) psychoses, he was particularly involved in applying Wernicke's syndromatic and Kraepelin's prognostic and aetiological principles to classify "neurogenous" psychoses by refuting the assumption of mixed entities whenever possible. Thus, has phasophrenias denoted manic-depressive illness, unipolar affective disorders and marginal, i.e., atypical psychoses. The rather benign cycloid psychoses form the most prominent examples of the latter. schizophrenias, on the other hand, were limited to poor long-term catamnestic outcomes. Kleist conceptualized the core group of schizophrenic illness as psychic system diseases-hence the origin of the term "systematic schizophrenias" within the Wernicke-Kleist-Leonhard School. Kleist was mainly influenced by Wernicke and his psychic reflex ARC, but Ernst Mach's empiriocriticism, Theodor Meynert's cerebral connectionism, and associationism also shaped his outlook. Kleist's localization of cerebral functions by lesion analyses was indeed the best available at the time and continues to reveal insights to the interested reader. From his Frankfurt School, which may have been the last of a completely unified neuropsychiatry, came sound representatives of psychiatry, neurology and neurosurgery. His technical mastery and achievements seem indisputable, but his balancing acts during the Third Reich may today be questioned. Despite joining the National Socialist German Workers' Party (NSDAP) and the local Court of Genealogical Health (Erbgesundheitsgericht), Kleist was, however, one of the few German physicians who continued to treat Jewish patients, to employ Jewish colleagues and to voice evident criticism of the policies of "eugenics" and "euthanasia". This paper attempts to illuminate Kleist's biography and life's work in the relevant historical context. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 4 | Hist Psychiatry 2003 Dec 14: 411-58 |
| PMID | 14740633 |
| Title | Karl Kleist (1879-1960)- a pioneer of neuropsychiatry. |
| Abstract | Karl Kleist (1879-1960) was instrumental in pioneering German neuropsychiatry and neuropsychology, including the description of frontal, constructional, limb-kinetic (innervatory) and psychomotor apraxias, frontal akinesia and aspontaneity, as well as object and form blindness. Besides isolating episodic twilight states, involutional paranoia and symptomatic (especially influenza) psychoses, he was particularly involved in applying Wernicke's syndromatic and Kraepelin's prognostic and aetiological principles to classify "neurogenous" psychoses by refuting the assumption of mixed entities whenever possible. Thus, has phasophrenias denoted manic-depressive illness, unipolar affective disorders and marginal, i.e., atypical psychoses. The rather benign cycloid psychoses form the most prominent examples of the latter. schizophrenias, on the other hand, were limited to poor long-term catamnestic outcomes. Kleist conceptualized the core group of schizophrenic illness as psychic system diseases-hence the origin of the term "systematic schizophrenias" within the Wernicke-Kleist-Leonhard School. Kleist was mainly influenced by Wernicke and his psychic reflex ARC, but Ernst Mach's empiriocriticism, Theodor Meynert's cerebral connectionism, and associationism also shaped his outlook. Kleist's localization of cerebral functions by lesion analyses was indeed the best available at the time and continues to reveal insights to the interested reader. From his Frankfurt School, which may have been the last of a completely unified neuropsychiatry, came sound representatives of psychiatry, neurology and neurosurgery. His technical mastery and achievements seem indisputable, but his balancing acts during the Third Reich may today be questioned. Despite joining the National Socialist German Workers' Party (NSDAP) and the local Court of Genealogical Health (Erbgesundheitsgericht), Kleist was, however, one of the few German physicians who continued to treat Jewish patients, to employ Jewish colleagues and to voice evident criticism of the policies of "eugenics" and "euthanasia". This paper attempts to illuminate Kleist's biography and life's work in the relevant historical context. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 5 | Neuropharmacology 2004 Jun 46: 1070-81 |
| PMID | 15111013 |
| Title | Enhanced dizocilpine efficacy in heterozygous reeler mice relates to GABA turnover downregulation. |
| Abstract | Reelin synthesized by cortical GABAergic interneurons throughout the telencephalon is secreted into the extracellular matrix (ECM) and binds with nM affinity to integrin receptors located at dendritic spine postsynaptic densities and positively modulates ARC and other dendritic resident mRNAs translation, thereby facilitating the onset of synaptic plasticity and LTP consolidation. Accordingly, the reelin haploinsufficient heterozygous reeler mice (HRM) express a marked decrease of cortical thickness, of cortical and hippocampal dendritic spine density, and of cortical GAD67 expression. Behaviorally, HRM manifest a sensorimotor deficit, an exaggerated response to fear, and a deficit in olfactory discrimination learning. HRM and wild-type mice (WTM) were trained to retrieve to criterion palatable chocolate-flavored food pellets in an eight-arm radial maze. In 9-14 days of training HRM and WTM learned the task equally well committing only a few errors. However, HRM, when compared with WTM, show a greater cognitive impairment following the administration of dizocilpine. Also, HRM are more susceptible to the increased locomotion and stereotypic behavior elicited by dizolcipine. The enhanced dizocilpine susceptibility of HRM is not due to differences in pharmacokinetics because the levels of dizocilpine in cortices of HRM and WTM were virtually equal. We also failed to detect differences between HRM and WTM in glutamate brain content and in the rate of 13C-glucose incorporation into the glutamate brain pools. In contrast we found that the conversion index of glutamate into GABA (an indirect measurement of GABA turnover rate) is decreased in cortex, hippocampus and striatum of HRM when compared to WTM. Thus, HRM recapitulate several neurochemical and behavioral endophenotypes reminiscent of schizophrenia and these mice can be proposed as a relevant animal model for the study of pharmacological treatments aimed at alleviating the sensory-motor and cognitive dysregulation associated with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 6 | Med. Hypotheses 2005 -1 65: 766-84 |
| PMID | 15953692 |
| Title | A scientific paradigm for consciousness: a theory of premotor relations. |
| Abstract | Consciousness has become a holy grail for scientific reseARCh only in the last few decades. In spite of the extensive recent reseARCh in the field agreement on a correct approach to a theory has been elusive. We all have an intuitive idea of what we mean by the term and at the very least relate awareness to a descriptive phenomenology. I present a theory of consciousness based on motor capacity. An organism may exert control through movement and any action it performs on its surroundings results in a reaction. This type of reafference generated by movement provides the organism with a unique opportunity to compare perceptual information, for example, a retinal image of a ball with what the body is telling the agent about the object. In other words, limb movements will describe a certain physical distance to the object and the shape will be conveyed by the ARC described around it by any part of the body that comes into contact with it. The reafference, also called motor efference copy, can modulate neocortical networks strictly associated with concurrent perceptual information via input to thalamocortical projections. Concurrent perceptual and motor reafferent input provide the critical organizing principles bestowing on a neural assembly the capacity of conscious awareness. The cortical neural coding represents an interactive history and is what I call a premotor relation. It avoids the trap of behaviorism by emphasizing a developmental causality such that, once the networks are established no further motoric component is required. Supportive evidence for this position comes from the classic psychological studies of perceptual adaptation to distorting lenses facilitated by movement and elegant animal experiments dissociating sensorimotor development from visual exposure. One of the most innovative and useful conceptions advanced in the paper is a component theory of motor efference copy analyzing the two key parameters of any action namely force and proprioceptive change. There is massive neocortical input to the basal ganglia and cerebellum and recent reseARCh has implicated cognitive roles for these structures. I propose they serve the respective component parameters of motor efference copy. Finally, a theory of premotor relations provides a model for understanding how dysfunction in the basal ganglia and cerebellum relates to cognitive features of schizophrenia and autism, respectively. Motor dysfunction figures prominently in the early literature on these syndromes and I make the case for a fundamental causal connection between motor and cognitive symptoms. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 7 | PLoS ONE 2006 -1 1: e61 |
| PMID | 17183692 |
| Title | Self-correcting maps of molecular pathways. |
| Abstract | Reliable and comprehensive maps of molecular pathways are indispensable for guiding complex biomedical experiments. Such maps are typically assembled from myriads of disparate reseARCh reports and are replete with inconsistencies due to variations in experimental conditions and/or errors. It is often an intractable task to manually verify internal consistency over a large collection of experimental statements. To automate large-scale reconciliation efforts, we propose a random-ARCs-and-nodes model where both nodes (tissue-specific states of biological molecules) and ARCs (interactions between them) are represented with random variables. We show how to obtain a non-contradictory model of a molecular network by computing the joint distribution for ARC and node variables, and then apply our methodology to a realistic network, generating a set of experimentally testable hypotheses. This network, derived from an automated analysis of over 3,000 full-text reseARCh articles, includes genes that have been hypothetically linked to four neurological disorders: Alzheimer's disease, autism, bipolar disorder, and schizophrenia. We estimated that approximately 10% of the published molecular interactions are logically incompatible. Our approach can be directly applied to an array of diverse problems including those encountered in molecular biology, ecology, economics, politics, and sociology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 8 | Psychopathology 2007 -1 40: 229-35 |
| PMID | 17396049 |
| Title | The temporal structure of intentionality and its disturbance in schizophrenia. |
| Abstract | Working memory, attention and executive control functions are central areas of neuropsychological reseARCh in schizophrenia. These concepts implicitly refer to the basic temporal structure of mental life as an integration of past, present and future. From a phenomenological point of view, they may be paralleled to the structure of internal time consciousness as analyzed by Husserl, consisting of a retentional, presentational and protentional function. These synthetic functions, operating at the most basic layer of consciousness, are capable of integrating the sequence of single moments into an 'intentional ARC', enabling us to direct ourselves towards objects and goals in a meaningful way. On this background, basic symptoms of schizophrenia such as formal thought disorder, loss of automatic performances and disturbances of self-awareness may be conceived as caused by a weakening and dissolution of the intentional ARC. A failure of the continuous intertwining of succeeding moments, and especially of the protentional function, leads to a loss of the tacit or operative intentionality that carries the acts of perceiving, thinking and acting. The loss of tacit, implicit functions undermines the common-sensical understanding of reality and has to be compensated by the deliberate, hyperreflexive reconstruction of everyday performances. Phenomenological analyses may thus establish a link between experimental reseARCh on single mental dysfunctions on the one hand and the higher level of the patient's subjective experience on the other. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 9 | J. Psychopharmacol. (Oxford) 2008 Jul 22: 536-42 |
| PMID | 18208916 |
| Title | Differential expression of IEG mRNA in rat brain following acute treatment with clozapine or haloperidol: a semi-quantitative RT-PCR study. |
| Abstract | Antipsychotic drugs have been shown to modulate immediate early gene (IEG) expression in rat brain regions that are associated with schizophrenia, which may be directly linked to their immediate therapeutic benefit. In this study, we analysed the expression profile of a series of IEGs (c-fos, c-jun, fra-1, Krox-20, Krox-24, ARC, sgk-1, BDNF and NARP) in six rat brain regions (prefrontal cortex, hippocampus, striatum, nucleus accumbens, thalamus and cerebellum). Rats (n=5) were administered either clozapine (20 mg/kg i.p.), haloperidol (1 mg/kg i.p.) or the appropriate vehicle with pre-treatment times of 1, 6 and 24 h. IEG expression was analysed in these regions by Taqman RT-PCR. The spatial and temporal profile of IEG induction following antipsychotic drug treatment correlates with regions associated with the efficacy and side effect profile of each drug. In particular, sgk-1 expression levels after antipsychotic drug treatment may have predictive value when investigating the profile of a novel antipsychotic drug. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 10 | Neuroscience 2008 Jun 154: 741-53 |
| PMID | 18495359 |
| Title | The selective alpha7 nicotinic acetylcholine receptor agonist A-582941 activates immediate early genes in limbic regions of the forebrain: Differential effects in the juvenile and adult rat. |
| Abstract | Due to the cognitive-enhancing properties of alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists, they have attracted interest for the treatment of cognitive disturbances in schizophrenia. schizophrenia typically presents in late adolescence or early adulthood. It is therefore important to study whether alpha7 nAChR stimulation activates brain regions involved in cognition in juvenile as well as adult individuals. Here, we compared the effects of the novel and selective alpha7 nAChR agonist 2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole (A-582941) in the juvenile and adult rat forebrain using two markers, activity-regulated cytoskeleton-associated protein (ARC) and c-Fos, to map neuronal activity. Acute administration of A-582941 (1, 3, 10 mg/kg) induced a dose-dependent increase in ARC mRNA expression in the medial prefrontal cortex (mPFC) and the ventral/lateral orbitofrontal (VO/LO) cortex of juvenile, but not adult rats. This effect was mitigated by the alpha7 nAChR antagonist methyllycaconitine. A-582941 also increased c-Fos mRNA expression in the mPFC of juvenile, but not adult rats. Furthermore, A-582941 increased the number of ARC and c-Fos immunopositive cells in the mPFC, VO/LO, and shell of the nucleus accumbens, in both juvenile and adult rats. The A-582941-induced c-Fos protein expression was significantly greater in the mPFC and VO/LO of juvenile compared with adult rats. These data indicate that A-582941-induced alpha7 nAChR stimulation activates brain regions critically involved in working memory and attention. Furthermore, this effect is more pronounced in juvenile than adult rats, indicating that the juvenile forebrain is more responsive to alpha7 nAChR stimulation. This observation may be relevant in the treatment of juvenile-onset schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 11 | Front Behav Neurosci 2009 -1 3: 20 |
| PMID | 19750198 |
| Title | Neural activity changes underlying the working memory deficit in alpha-CaMKII heterozygous knockout mice. |
| Abstract | The alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII) is expressed abundantly in the forebrain and is considered to have an essential role in synaptic plasticity and cognitive function. Previously, we reported that mice heterozygous for a null mutation of alpha-CaMKII (alpha-CaMKII+/-) have profoundly dysregulated behaviors including a severe working memory deficit, which is an endophenotype of schizophrenia and other psychiatric disorders. In addition, we found that almost all the neurons in the dentate gyrus (DG) of the mutant mice failed to mature at molecular, morphological and electrophysiological levels. In the present study, to identify the brain substrates of the working memory deficit in the mutant mice, we examined the expression of the immediate early genes (IEGs), c-Fos and ARC, in the brain after a working memory version of the eight-arm radial maze test. c-Fos expression was abolished almost completely in the DG and was reduced significantly in neurons in the CA1 and CA3 areas of the hippocampus, central amygdala, and medial prefrontal cortex (mPFC). However, c-Fos expression was intact in the entorhinal and visual cortices. Immunohistochemical studies using ARC promoter driven dVenus transgenic mice demonstrated that ARC gene activation after the working memory task occurred in mature, but not immature neurons in the DG of wild-type mice. These results suggest crucial insights for the neural circuits underlying spatial mnemonic processing during a working memory task and suggest the involvement of alpha-CaMKII in the proper maturation and integration of DG neurons into these circuits. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 12 | Eur. J. Pharmacol. 2009 Oct 620: 27-35 |
| PMID | 19695244 |
| Title | F15063, a potential antipsychotic with dopamine D(2)/D(3) receptor antagonist and 5-HT(1A) receptor agonist properties: influence on immediate-early gene expression in rat prefrontal cortex and striatum. |
| Abstract | Brain region-specific modulation of immediate-early gene (IEG) may constitute a marker of antipsychotic drug-like activity. We investigated the effects of the putative antipsychotic drug N-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy)ethyl]-3-(cyclopent-1-enyl)-benzylamine (F15063), a compound that targets both dopamine D(2) and serotonin 5-HT(1A) receptors, in comparison with haloperidol and clozapine on rat mRNA expression of IEG i.e. the zinc-fingered transcription factors c-fos, fosB, zif268, c-jun and junB, two transcription factors of the nuclear receptor family nur77 and nor1, and the effector IEG ARC. F15063 (10 mg/kg) and clozapine (10 mg/kg), but not haloperidol (0.63 mg/kg), induced c-fos and fosB mRNA expression in prefrontal cortex, a region associated with control of cognition and negative symptoms of schizophrenia. In striatum, only c-fos, fosB, junB and nur77 were induced by clozapine whereas all IEG mRNAs were increased by haloperidol and F15063 (from 2.5 mg/kg) with similar high efficacy despite a total absence of F15063-induced catalepsy. However, at 0.63 mg/kg, F15063 induced a lower degree of striatal IEG mRNA expression than haloperidol and pretreatment with the serotonin 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl-N-(2-pyridinyl)cyclohexane carboxamide trihydrochloride (WAY100635) (0.63 mg/kg) increased the level of IEG mRNA induction by F15063. Furthermore, (+)-8-hydroxy-2-(di-n-propylamino)tetralin [(+)-8-OH-DPAT] at 0.16 mg/kg decreased haloperidol-induced striatal IEG mRNA expression although it exerted no effects on its own. These results are consistent with an activation of serotonin 5-HT(1A) receptors by F15063, thus reducing D(2) blockade-induced striatal IEG mRNA. Furthermore, the substantial F15063-induced expression of IEGs such as c-fos in striatum is not related to cataleptogenic activity and may act more as a marker of efficacious dopamine D(2) receptor blockade. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 13 | Int. J. Neuropsychopharmacol. 2009 Mar 12: 243-55 |
| PMID | 18684341 |
| Title | Effects of repeated treatment of phencyclidine on cognition and gene expression in C57BL/6 mice. |
| Abstract | A number of studies indicate that glutamatergic N-methyl-D-aspartate (NMDA) neurotransmission is disturbed in schizophrenia partly based on the findings that NMDA receptor antagonists such as phencyclidine (PCP) can reproduce a schizophrenia-like syndrome in both humans and rodents. This study investigated whether repeated administration of low doses of PCP can induce cognitive dysfunctions in mice at doses which produce no sensorimotor disturbances. In addition, the effects on cognition were related to the expression of two genes, ARC and spinophilin, which have been related to neuronal plasticity and learning. Adult male C57Bl/6J mice received daily s.c. doses of PCP (0.5-2.0 mg/kg) or saline for 7 d. Testing was performed 24 h after the last day of treatment. Only the 2.0 mg/kg PCP dose produced a consistent impairment in spatial learning and working memory performed in the water-maze task without any apparent sensorimotor deficits. Importantly, the 2.0 mg/kg PCP dose produced no impairment in a non-spatial learning paradigm in the water-maze task. PCP treatment altered ARC mRNA levels in the hippocampus and retrosplenial agranular cortex while leaving the striatum and prefrontal cortex unaffected. The mRNA expression of spinophilin was down-regulated in striatum by repeated PCP treatment. These results demonstrate that repeated treatment with low doses of PCP in mice can produce specific cognitive deficits which are associated with alterations in gene expression in brain regions that appear to play a role in the pathophysiology of schizophrenia. These results suggest that the low-dose PCP model may have significant potential in characterizing the behavioural and molecular mechanisms underlying cognitive deficits seen in schizophrenia patients. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 14 | J. Neurochem. 2010 Aug 114: 1205-16 |
| PMID | 20533993 |
| Title | Repeated administration of alpha7 nicotinic acetylcholine receptor (nAChR) agonists, but not positive allosteric modulators, increases alpha7 nAChR levels in the brain. |
| Abstract | The alpha7 nicotinic acetylcholine receptor (nAChR) is an important target for treatment of cognitive deficits in schizophrenia and Alzheimer's disease. However, the receptor desensitizes rapidly in vitro, which has led to concern regarding its applicability as a clinically relevant drug target. Here we investigate the effects of repeated agonism on alpha7 nAChR receptor levels and responsiveness in vivo in rats. Using [(125)I]-alpha-bungarotoxin (BTX) autoradiography we show that acute or repeated administration with the selective alpha7 nAChR agonist A-582941 increases the number of alpha7 nAChR binding sites in several brain regions, particularly in the prefrontal cortex. The alpha7 nAChR agonists SSR180711 and PNU-282987 also increase [(125)I]-BTX binding, suggesting that this is a general consequence of alpha7 nAChR agonism. Interestingly, the alpha7 nAChR positive allosteric modulators PNU-120596 and NS1738 do not increase [(125)I]-BTX binding. Furthermore, A-582941-induced increase in ARC and c-fos mRNA expression in the prefrontal cortex is enhanced and unaltered, respectively, after repeated administration, demonstrating that the alpha7 nAChRs remain responsive. Contrarily, A-582941-induced phosphorylation of Erk2 in the prefrontal cortex occurs following acute, but not repeated administration. Our results demonstrate that repeated agonist administration increases the number of alpha7 nAChRs in the brain, and leads to coupling versus uncoupling of specific intracellular signaling pathways. Additionally, our data suggest a fundamental difference between the sequelae of repeated administration with agonists and allosteric modulators of the alpha7 nAChR. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 15 | J. Biol. Chem. 2010 Dec 285: 41380-90 |
| PMID | 20966073 |
| Title | Brain-specific Phgdh deletion reveals a pivotal role for L-serine biosynthesis in controlling the level of D-serine, an N-methyl-D-aspartate receptor co-agonist, in adult brain. |
| Abstract | In mammalian brain, D-serine is synthesized from L-serine by serine racemase, and it functions as an obligatory co-agonist at the glycine modulatory site of N-methyl-D-aspartate (NMDA)-selective glutamate receptors. Although diminution in D-serine level has been implicated in NMDA receptor hypofunction, which is thought to occur in schizophrenia, the source of the precursor L-serine and its role in D-serine metabolism in adult brain have yet to be determined. We investigated whether L-serine synthesized in brain via the phosphorylated pathway is essential for D-serine synthesis by generating mice with a conditional deletion of D-3-phosphoglycerate dehydrogenase (Phgdh; EC 1.1.1.95). This enzyme catalyzes the first step in L-serine synthesis via the phosphorylated pathway. HPLC analysis of serine enantiomers demonstrated that both L- and D-serine levels were markedly decreased in the cerebral cortex and hippocampus of conditional knock-out mice, whereas the serine deficiency did not alter protein expression levels of serine racemase and NMDA receptor subunits in these regions. The present study provides definitive proof that L-serine-synthesized endogenously via the phosphorylated pathway is a key rate-limiting factor for maintaining steady-state levels of D-serine in adult brain. Furthermore, NMDA-evoked transcription of ARC, an immediate early gene, was diminished in the hippocampus of conditional knock-out mice. Thus, this study demonstrates that in mature neuronal circuits L-serine availability determines the rate of D-serine synthesis in the forebrain and controls NMDA receptor function at least in the hippocampus. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 16 | Neurochem. Int. 2010 Dec 57: 756-61 |
| PMID | 20817066 |
| Title | ?7 nicotinic receptor agonism mitigates phencyclidine-induced changes in synaptophysin and Arc gene expression in the mouse prefrontal cortex. |
| Abstract | Repeated phencyclidine (PCP) administration in mice reproduces several histopathological features of schizophrenia, such as reduced synaptophysin and parvalbumin mRNA expression in the frontal cortex. These changes can be prevented by co-administering the ?7 nicotinic acetylcholine receptor (nAChR) agonist SSR180711 with PCP, but it is not known to what extent PCP-induced changes can be normalized once they have already occurred. Here we use semi-quantitative in situ hybridization to show that repeated administration of SSR180711 (3 mg/kg b.i.d. for 5 days) subsequent to repeated PCP administration (10 mg/kg/day for 10 days) is able to mitigate the reduction of synaptophysin mRNA expression induced by PCP in two prefrontal cortical regions, the medial prefrontal cortex (mPFC) and the ventrolateral orbitofrontal cortex (VLO). This effect is accompanied by a normalization of the PCP-induced increase in ARC mRNA expression in the same regions. In contrast, subsequent administration of SSR180711 does not affect PCP-induced decreases in parvalbumin mRNA in the mPFC, and glutamate decarboxylase 67 mRNA in the mPFC or VLO. These data demonstrate that it is possible to restore some, but not all, of the molecular dysregulations induced by repeated PCP administration with an ?7 nAChR agonist. They also suggest that the previously demonstrated cognitive improvement with SSR180711 subsequent to PCP treatment does not require normalization of parvalbumin expression, but may instead be related to a restoration of synaptophysin and/or ARC levels in the frontal cortex. These data lend support to the potential for development of ?7 nAChR agonists for the treatment of cognitive deficits in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 17 | Psychopharmacology (Berl.) 2010 Oct 212: 329-44 |
| PMID | 20652539 |
| Title | Divergent acute and chronic modulation of glutamatergic postsynaptic density genes expression by the antipsychotics haloperidol and sertindole. |
| Abstract | A pivotal role for glutamate in the pathophysiology and treatment of schizophrenia has been suggested. Few reports have investigated the impact of antipsychotics on postsynaptic density (PSD) molecules involved in glutamatergic transmission and synaptic remodeling. Homer is a key PSD molecule putatively implicated in schizophrenia. We studied the effect, in acute and chronic paradigms, of a first and a second generation antipsychotic (haloperidol and sertindole, respectively) on the expression of Homer1a and Homer-interacting PSD molecules. In the acute paradigm, Homer1a expression was induced by haloperidol but not sertindole in the striatum, consistent with the less propensity of sertindole to affect nigrostriatal neurotransmission. The profile of expression of two other inducible genes, Ania3 and ARC, was highly similar to Homer1a. In the cortex, haloperidol reduced Homer1a and induced Ania3. In the chronic paradigm, striatal expression of Homer1a and Ania3 resembled that observed in the acute paradigm. In the cortex, haloperidol induced Homer1a, while sertindole did not. Homer1b expression was increased by haloperidol in the striatum and cortex whereas sertindole selectively induced Homer1b in the cortex. The expression of mGluR5 was increased by both antipsychotics. A modulation by haloperidol was also seen for PSD-95 and ?CaMKII. These results suggest that haloperidol and sertindole may significantly modulate glutamatergic transcripts of the postsynaptic density. Sertindole induces constitutive genes in the cortex predominantly, which may correlate with its propensity to improve cognitive functions. Haloperidol preferentially modulates gene expression in the striatum, consistent with its action at nigrostriatal projections and its propensity to give motor side effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 18 | Front Behav Neurosci 2010 -1 4: 32 |
| PMID | 20589092 |
| Title | Ethanol and phencyclidine interact with respect to nucleus accumbens dopamine release: differential effects of administration order and pretreatment protocol. |
| Abstract | Executive dysfunction is a common symptom among alcohol-dependent individuals. Phencyclidine (PCP) injection induces dysfunction in the prefrontal cortex of animals but little is known about how PCP affects the response to ethanol. Using the in vivo microdialysis technique in male Wistar rats, we investigated how systemic injection of 5 mg/kg PCP would affect the dopamine release induced by local infusion of 300 mM ethanol into the nucleus accumbens. PCP given 60 min before ethanol entirely blocked ethanol-induced dopamine release. However, when ethanol was administered 60 min before PCP, both drugs induced dopamine release and PCP's effect was potentiated by ethanol (180% increase vs 150%). To test the role of prefrontal cortex dysfunction in ethanol reinforcement, animals were pretreated for 5 days with 2.58 mg/kg PCP according to previously used 'PFC hypofunction protocols'. This, however, did not change the relative response to PCP or ethanol compared to saline-treated controls. qPCR illustrated that this low PCP dose did not significantly change expression of glucose transporters Glut1 (SLC2A1) or Glut3 (SLC2A3), monocarboxylate transporter MCT2 (SLC16A7), glutamate transporters GLT-1 (SLC1A2) or GLAST (SLC1A3), the immediate early gene ARC (Arg3.1) or GABAergic neuron markers GAT-1 (SLC6A1) and parvalbumin. Therefore, we concluded that PCP at a dose of 2.58 mg/kg for 5 days did not induce hypofunction in Wistar rats. However, PCP and ethanol do have overlapping mechanisms of action and these drugs differentially affect mesolimbic dopaminergic transmission depending on the order of administration. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 19 | Neurochem. Int. 2010 Jan 56: 270-5 |
| PMID | 19897002 |
| Title | Opposite effect of phencyclidine on activity-regulated cytoskeleton-associated protein (Arc) in juvenile and adult limbic rat brain regions. |
| Abstract | The psychotomimetic effect of NMDA antagonists such as phencyclidine (PCP) in humans spurred the hypoglutamatergic theory of schizophrenia. This theory is supported by animal studies demonstrating schizophrenia-like behavioral and molecular changes following PCP administration to adult or neonatal animals. However, schizophrenia is believed to develop in part due to neurodevelopmental dysfunction during adolescence. Therefore, the effects of PCP in juvenile animals may better reflect the pathophysiology of schizophrenia. Here, we compare the effect of PCP (5mg/kg/day for 5 days) on activity-regulated cytoskeleton-associated protein (ARC) and parvalbumin mRNA expression in juvenile and adult rats. ARC is a marker for excitatory neurotransmission. Parvalbumin is a marker for GABAergic neurotransmission, known to be reduced in postmortem brains of schizophrenics. PCP reduced parvalbumin mRNA expression in the medial prefrontal cortex (mPFC), ventrolateral orbitofrontal cortex (VLO) and shell of the nucleus accumbens (ACCshell) in both juvenile and adult rats. Contrarily, PCP produced opposite effects on ARC mRNA expression in the mPFC, VLO and ACCshell, leading to decreased expression in juvenile and increased expression in adult rats. The differential effect of PCP in juvenile and adult rats may be caused by the immature functional state of the prefrontal cortex in juvenile rats. These results demonstrate differences between the effects of PCP in juvenile and adult rats. The decrease in ARC mRNA in juvenile rats corresponds best with the proposed "hypofrontality" in schizophrenia, suggesting the merits of using PCP in juvenile animals as a model for schizophrenia, as this would relate better to the typical onset and clinical features of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 20 | Neurochem. Int. 2010 Jan 56: 270-5 |
| PMID | 19897002 |
| Title | Opposite effect of phencyclidine on activity-regulated cytoskeleton-associated protein (Arc) in juvenile and adult limbic rat brain regions. |
| Abstract | The psychotomimetic effect of NMDA antagonists such as phencyclidine (PCP) in humans spurred the hypoglutamatergic theory of schizophrenia. This theory is supported by animal studies demonstrating schizophrenia-like behavioral and molecular changes following PCP administration to adult or neonatal animals. However, schizophrenia is believed to develop in part due to neurodevelopmental dysfunction during adolescence. Therefore, the effects of PCP in juvenile animals may better reflect the pathophysiology of schizophrenia. Here, we compare the effect of PCP (5mg/kg/day for 5 days) on activity-regulated cytoskeleton-associated protein (ARC) and parvalbumin mRNA expression in juvenile and adult rats. ARC is a marker for excitatory neurotransmission. Parvalbumin is a marker for GABAergic neurotransmission, known to be reduced in postmortem brains of schizophrenics. PCP reduced parvalbumin mRNA expression in the medial prefrontal cortex (mPFC), ventrolateral orbitofrontal cortex (VLO) and shell of the nucleus accumbens (ACCshell) in both juvenile and adult rats. Contrarily, PCP produced opposite effects on ARC mRNA expression in the mPFC, VLO and ACCshell, leading to decreased expression in juvenile and increased expression in adult rats. The differential effect of PCP in juvenile and adult rats may be caused by the immature functional state of the prefrontal cortex in juvenile rats. These results demonstrate differences between the effects of PCP in juvenile and adult rats. The decrease in ARC mRNA in juvenile rats corresponds best with the proposed "hypofrontality" in schizophrenia, suggesting the merits of using PCP in juvenile animals as a model for schizophrenia, as this would relate better to the typical onset and clinical features of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 21 | PLoS ONE 2011 -1 6: e20571 |
| PMID | 21695181 |
| Title | Olanzapine-induced hyperphagia and weight gain associate with orexigenic hypothalamic neuropeptide signaling without concomitant AMPK phosphorylation. |
| Abstract | The success of antipsychotic drug treatment in patients with schizophrenia is limited by the propensity of these drugs to induce hyperphagia, weight gain and other metabolic disturbances, particularly evident for olanzapine and clozapine. However, the molecular mechanisms involved in antipsychotic-induced hyperphagia remain unclear. Here, we investigate the effect of olanzapine administration on the regulation of hypothalamic mechanisms controlling food intake, namely neuropeptide expression and AMP-activated protein kinase (AMPK) phosphorylation in rats. Our results show that subchronic exposure to olanzapine upregulates neuropeptide Y (NPY) and agouti related protein (AgRP) and downregulates proopiomelanocortin (POMC) in the ARCuate nucleus of the hypothalamus (ARC). This effect was evident both in rats fed ad libitum and in pair-fed rats. Of note, despite weight gain and increased expression of orexigenic neuropeptides, subchronic administration of olanzapine decreased AMPK phosphorylation levels. This reduction in AMPK was not observed after acute administration of either olanzapine or clozapine. Overall, our data suggest that olanzapine-induced hyperphagia is mediated through appropriate changes in hypothalamic neuropeptides, and that this effect does not require concomitant AMPK activation. Our data shed new light on the hypothalamic mechanism underlying antipsychotic-induced hyperphagia and weight gain, and provide the basis for alternative targets to control energy balance. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 22 | Schizophr. Res. 2011 Aug 130: 260-5 |
| PMID | 21576009 |
| Title | Endosomal trafficking of AMPA receptors in frontal cortex of elderly patients with schizophrenia. |
| Abstract | Several lines of evidence indicate altered trafficking of ?-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors in schizophrenia. Previous reports have implicated alterations in the endosomal trafficking of AMPA receptors in this illness. We hypothesized that late endosome content of AMPA receptor subunits is altered in schizophrenia. Accordingly, we developed a technique to isolate and measure contents of late endosomes from postmortem human tissue. We found no changes in the expression of the AMPA subunits, GluR1-4, in late endosomes from the dorsolateral prefrontal cortex in schizophrenia. We also hypothesized that proteins involved in the sorting and trafficking of AMPA receptors between endosomal compartments would be altered in schizophrenia. We found no changes in expression of multiple proteins associated with these processes (dynamin3, ARC/ARG3.1, NEEP21, GRASP1, liprin ?, and syntaxin13). Together, these data suggest that endosomal trafficking of AMPA receptors in the prefrontal cortex may be largely intact in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 23 | Hippocampus 2011 Sep 21: 1028-35 |
| PMID | 20572199 |
| Title | AMPA GluR-A receptor subunit mediates hippocampal responsiveness in mice exposed to stress. |
| Abstract | Because stress represents a major precipitating event for psychiatric disorders, it is important to identify molecular mechanisms that may be altered in vulnerable individuals when exposed to stress. Here, we studied GluR-A(-/-) mice, animals with compromised AMPA receptor signaling, and characterized by a schizophrenic as well as depressive phenotype to investigate changes occurring in response to an acute stress. Wild-type and GluR-A(-/-) mice were exposed to a single immobilization stress and sacrificed immediately after the end of the stress for the analysis of activity regulated genes and of glutamatergic synapse responsiveness. The acute stress produced a marked increase in the hippocampal expression of ARC (activity-regulated cytoskeletal-associated protein) in GluR-A(-/-) , but not in wild-type mice, which was associated with a similar increase of phospho-CaMKII, a partner in the action of ARC. When looking at the glutamatergic response to stress in wild-type animals, we found that stress increased GluR-A phosphorylation on serine831, an effect that was paralleled by a significant increase of the phosphorylation of the main NMDA receptor subunits, that is, NR-1 and NR-2B. Conversely, the stress-induced modulation of NMDA receptor subunits was not observed in GluR-A(-/-) mice. We suggest that enhanced stress responsiveness in GluR-A(-/-) mice may be due, at least in part, to their inability to activate NMDA-mediated glutamatergic neurotransmission, suggesting that the integrity of AMPA/NMDA receptor function may be important for successful coping under stressful conditions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 24 | Neurosci. Res. 2012 Dec 74: 195-9 |
| PMID | 23116567 |
| Title | Enhanced MK-801-induced locomotion in Kir6.2 knockout mice. |
| Abstract | ATP-sensitive K(+) (K-ATP) channels provide a unique link between cellular energetics and electrical excitability, and also act as a unifying molecular coordinator of the body's response to stress. Although the body's response to stress is implicated in the worsening or relapse of psychotic symptoms in schizophrenia, the role of K-ATP channels remains unclear. Therefore, the aim of the current study was to investigated the effect of K-ATP channels on schizophrenia-like symptoms induced by MK-801 using Kir6.2 (one pore-forming subunit of K-ATP) knockout mice. We demonstrated that Kir6.2 knockout enhanced locomotor activity significantly compared to the wild-type mice after MK-801 administration. Moreover, we found that depletion of Kir6.2 significantly increased the numbers of ARC-positive cells in cortex, hippocampus and striatum in basal state. MK-801 augmented the ARC expression in wild-type mice. Collectively, our findings in this study indicate that K-ATP channels are involved in the regulation of MK-801-induced acute symptoms of schizophrenia, which is associated with the neural excitability. In addition, our results may provide valuable information for the development of new treatments for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 25 | Proc. Natl. Acad. Sci. U.S.A. 2012 Jun 109: 9617-22 |
| PMID | 22645329 |
| Title | Erythropoietin-induced changes in brain gene expression reveal induction of synaptic plasticity genes in experimental stroke. |
| Abstract | Erythropoietin (EPO) is a neuroprotective cytokine in models of ischemic and nervous system injury, where it reduces neuronal apoptosis and inflammatory cytokines and increases neurogenesis and angiogenesis. EPO also improves cognition in healthy volunteers and schizophrenic patients. We studied the effect of EPO administration on the gene-expression profile in the ischemic cortex of rats after cerebral ischemia at early time points (2 and 6 h). EPO treatment up-regulated genes already increased by ischemia. HierARChical clustering and analysis of overrepresented functional categories identified genes implicated in synaptic plasticity-ARC, BDNF, Egr1, and Egr2, of which Egr2 was the most significantly regulated. Up-regulation of ARC, BDNF, Dusp5, Egr1, Egr2, Egr4, and Nr4a3 was confirmed by quantitative PCR. We investigated the up-regulation of Egr2/Krox20 further because of its role in neuronal plasticity. Its elevation by EPO was confirmed in an independent in vivo experiment of cerebral ischemia in rats. Using the rat neuroblastoma B104, we found that wild-type cells that do not express EPO receptor (EPOR) do not respond to EPO by inducing Egr2. However, EPOR-expressing B104 cells induce Egr2 early upon incubation with EPO, indicating that Egr2 induction is a direct effect of EPO and that EPOR mediates this effect. Because these changes occur in vivo before decreased inflammatory cytokines or neuronal apoptosis is evident, these findings provide a molecular mechanism for the neuroreparative effects of cytokines and suggest a mechanism of neuroprotection by which promotion of a plastic phenotype results in decreased inflammation and neuronal death. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 26 | Front Pharmacol 2012 -1 3: 189 |
| PMID | 23125836 |
| Title | Group I metabotropic glutamate receptor-mediated gene transcription and implications for synaptic plasticity and diseases. |
| Abstract | Stimulation of group I metabotropic glutamate receptors (mGluRs) initiates a wide variety of signaling pathways. Group I mGluR activation can regulate gene expression at both translational and transcriptional levels, and induces translation or transcription-dependent synaptic plastic changes in neurons. The group I mGluR-mediated translation-dependent neural plasticity has been well reviewed. In this review, we will highlight group I mGluR-induced gene transcription and its role in synaptic plasticity. The signaling pathways (PKA, CaMKs, and MAPKs) which have been shown to link group I mGluRs to gene transcription, the relevant transcription factors (CREB and NF-?B), and target proteins (FMRP and ARC) will be documented. The significance and future direction for characterizing group I mGluR-mediated gene transcription in fragile X syndrome, schizophrenia, drug addiction, and other neurological disorders will also be discussed. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 27 | Eur Neuropsychopharmacol 2012 May 22: 364-73 |
| PMID | 21982116 |
| Title | Effects of olanzapine on muscarinic M3 receptor binding density in the brain relates to weight gain, plasma insulin and metabolic hormone levels. |
| Abstract | The second generation antipsychotic drug (SGA) olanzapine has an efficacy to treat schizophrenia, but can cause obesity and type II diabetes mellitus. Cholinergic muscarinic M3 receptors (M3R) are expressed on pancreatic ?-cells and in the brain where they influence insulin secretion and may regulate other metabolic hormones via vagal innervation of the gastrointestinal tract. Olanzapine's M3R antagonism is an important risk factor for its diabetogenic liability. However, the effects of olanzapine on central M3Rs are unknown. Rats were treated with 0.25, 0.5, 1.0 or 2.0 mg olanzapine/kg or vehicle (3×/day, 14-days). M3R binding densities in the hypothalamic ARCuate (ARC) and ventromedial nuclei (VMH), and dorsal vagal complex (DVC) of the brainstem were investigated using [3H]4-DAMP plus pirenzepine and AF-DX116. M3R binding correlations to body weight, food intake, insulin, ghrelin and cholecystokinin (CCK) were analyzed. Olanzapine increased M3R binding density in the ARC, VMH and DVC, body weight, food intake, circulating plasma ghrelin and CCK levels, and decreased plasma insulin and glucose. M3R negatively correlated to insulin, and positively correlated to ghrelin, CCK, food intake and body weight. Increased M3R density is a compensatory up-regulation in response to olanzapine's M3R antagonism. Olanzapine acts on M3R in regions of the brain that control food intake and insulin secretion. Olanzapine's M3R blockade in the brain may inhibit the acetylcholine pathway for insulin secretion. These findings support a role for M3Rs in the modulation of insulin, ghrelin and CCK via the vagus nerve and provide a mechanism for olanzapine's diabetogenic and weight gain liability. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 28 | PLoS ONE 2012 -1 7: e33548 |
| PMID | 22438946 |
| Title | Alterations to melanocortinergic, GABAergic and cannabinoid neurotransmission associated with olanzapine-induced weight gain. |
| Abstract | Second generation antipsychotics (SGAs) are used to treat schizophrenia but can cause serious metabolic side-effects, such as obesity and diabetes. This study examined the effects of low to high doses of olanzapine on appetite/metabolic regulatory signals in the hypothalamus and brainstem to elucidate the mechanisms underlying olanzapine-induced obesity. Levels of pro-opiomelanocortin (POMC), neuropeptide Y (NPY) and glutamic acid decarboxylase (GAD(65), enzyme for GABA synthesis) mRNA expression, and cannabinoid CB1 receptor (CB1R) binding density (using [(3)H]SR-141716A) were examined in the ARCuate nucleus (ARC) and dorsal vagal complex (DVC) of female Sprague Dawley rats following 0.25, 0.5, 1.0 or 2.0 mg/kg olanzapine or vehicle (3×/day, 14-days). Consistent with its weight gain liability, olanzapine significantly decreased anorexigenic POMC and increased orexigenic NPY mRNA expression in a dose-sensitive manner in the ARC. GAD(65) mRNA expression increased and CB1R binding density decreased in the ARC and DVC. Alterations to neurotransmission signals in the brain significantly correlated with body weight and adiposity. The minimum dosage threshold required to induce weight gain in the rat was 0.5 mg/kg olanzapine. Olanzapine-induced weight gain is associated with reduced appetite-inhibiting POMC and increased NPY. This study also supports a role for the CB1R and GABA in the mechanisms underlying weight gain side-effects, possibly by altering POMC transmission. Metabolic dysfunction can be modelled in the female rat using low, clinically-comparable olanzapine doses when administered in-line with the half-life of the drug. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 29 | Mol. Psychiatry 2012 Feb 17: 142-53 |
| PMID | 22083728 |
| Title | De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. |
| Abstract | A small number of rare, recurrent genomic copy number variants (CNVs) are known to substantially increase susceptibility to schizophrenia. As a consequence of the low fecundity in people with schizophrenia and other neurodevelopmental phenotypes to which these CNVs contribute, CNVs with large effects on risk are likely to be rapidly removed from the population by natural selection. Accordingly, such CNVs must frequently occur as recurrent de novo mutations. In a sample of 662 schizophrenia proband-parent trios, we found that rare de novo CNV mutations were significantly more frequent in cases (5.1% all cases, 5.5% family history negative) compared with 2.2% among 2623 controls, confirming the involvement of de novo CNVs in the pathogenesis of schizophrenia. Eight de novo CNVs occurred at four known schizophrenia loci (3q29, 15q11.2, 15q13.3 and 16p11.2). De novo CNVs of known pathogenic significance in other genomic disorders were also observed, including deletion at the TAR (thrombocytopenia absent radius) region on 1q21.1 and duplication at the WBS (Williams-Beuren syndrome) region at 7q11.23. Multiple de novos spanned genes encoding members of the DLG (discs large) family of membrane-associated guanylate kinases (MAGUKs) that are components of the postsynaptic density (PSD). Two de novos also affected EHMT1, a histone methyl transferase known to directly regulate DLG family members. Using a systems biology approach and merging novel CNV and proteomics data sets, systematic analysis of synaptic protein complexes showed that, compared with control CNVs, case de novos were significantly enriched for the PSD proteome (P=1.72 × 10??. This was largely explained by enrichment for members of the N-methyl-D-aspartate receptor (NMDAR) (P=4.24 × 10??) and neuronal activity-regulated cytoskeleton-associated protein (ARC) (P=3.78 × 10??) postsynaptic signalling complexes. In an analysis of 18?492 subjects (7907 cases and 10?585 controls), case CNVs were enriched for members of the NMDAR complex (P=0.0015) but not ARC (P=0.14). Our data indicate that defects in NMDAR postsynaptic signalling and, possibly, ARC complexes, which are known to be important in synaptic plasticity and cognition, play a significant role in the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 30 | Neuroscience 2013 Oct 250: 222-31 |
| PMID | 23872394 |
| Title | Effects of withdrawal from repeated amphetamine exposure in peri-puberty on neuroplasticity-related genes in mice. |
| Abstract | Although extensive evidence demonstrates that repeated administration of amphetamine (AMPH) induces behavioral and neurochemical sensitization, the influence of the developmental timing of AMPH administration is unknown. This is an important issue to address because it could help clarify the influence of early drug exposure on neuronal plasticity and the involvement of dopaminergic sensitization in the etiopathology of neuropsychiatric disorders. Thus, we decided to investigate the molecular alterations induced by the administration of AMPH during adolescence, when repeated exposure to the psychostimulant may interfere with developmental neuroplasticity. We investigated the expression of the neurotrophin brain-derived neurotrophic factor (BDNF) and of two inducible-early genes (ARC and cfos) that bridge neuronal activity with long-lasting functional alterations. We found that peri-pubertal treatment with AMPH induces long-lasting changes in the expression of bdnf and of activity-regulated genes in the hippocampus and in the prefrontal/frontal cortex, and leads to alterations of their short-term modulation in response to a subsequent acute AMPH challenge. These data suggest that AMPH exposure in peri-puberty may negatively affect the maturation of brain structures, such as the prefrontal cortex, which facilitate the development of dopamine sensitization and may contribute to dopamine-dependent behavioral dysfunctions and molecular alterations in adulthood. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 31 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2013 Oct 46: 1-12 |
| PMID | 23800465 |
| Title | Different effects of the NMDA receptor antagonists ketamine, MK-801, and memantine on postsynaptic density transcripts and their topography: role of Homer signaling, and implications for novel antipsychotic and pro-cognitive targets in psychosis. |
| Abstract | Administration of NMDA receptor antagonists, such as ketamine and MK-801, may induce psychotic-like behaviors in preclinical models of schizophrenia. Ketamine has also been observed to exacerbate psychotic symptoms in schizophrenia patients. However, memantine, a non-competitive NMDA receptor antagonist approved for Alzheimer's disease and proposed for antipsychotic augmentation, may challenge this view. To date, the molecular mechanisms by which these NMDA receptor antagonists cause different neurochemical, behavioral, and clinical effects are still a matter of debate. Here, we investigated by molecular imaging whether these agents could differently modulate gene expression and topographical distribution of glutamatergic postsynaptic density (PSD) proteins. We focused on Homer1a/Homer1b/PSD-95 signaling network, which may be implicated in glutamate-dependent synaptic plasticity, as well as in psychosis pathophysiology and treatment. Ketamine (25 and 50mg/kg) and MK-801 (0.8mg/kg) significantly induced the transcripts of immediate-early genes (ARC, c-fos, and Homer1a) in cortical regions compared to vehicle, whereas they reduced Homer1b and PSD-95 expression in cortical and striatal regions. Differently, memantine (5mg/kg) did not increase Homer1a signal compared to vehicle, whereas it induced c-fos in the somatosensory and in the medial agranular cortices. Moreover, memantine did not affect Homer1b and PSD-95 expression. When compared to ketamine and MK-801, memantine significantly increased the expression of c-fos, Homer1b and PSD-95. Overall, ketamine and MK-801 prominently increased Homer1a/Homer1b expression ratio, whereas memantine elicited the opposite effect. These data may support the view that ketamine, MK-801 and memantine exert divergent effects on PSD transcripts, which may contribute to their partially different behavioral and clinical effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 32 | J. Neurosci. Res. 2013 May 91: 634-41 |
| PMID | 23404493 |
| Title | Enhanced prefrontal serotonin 2A receptor signaling in the subchronic phencyclidine mouse model of schizophrenia. |
| Abstract | Prefrontal serotonin 2A receptors (5-HT2A Rs) have been linked to the pathogenesis and treatment of schizophrenia. Many antipsychotics fully occupy 5-HT2A R at clinical relevant doses, and activation of 5-HT2A receptors by lysergic acid diethylamide (LSD) and LSD-like drugs induces a schizophrenia-like psychosis in humans. Subchronic phencyclidine (PCP) administration is a well-established model for schizophrenia-like symptoms in rodents. The aim of the present study was to investigate whether subchronic PCP administration changes expression, binding, or functionality of cortical 5-HT2A Rs. As a measure of 5-HT2A R functionality, we used the 5-HT2A R agonist 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced head-twitch response (HTR) and mRNA expression of the immediate-early genes (IEGs) activity-related cytoskeletal associated-protein (ARC), c-fos, and early growth response protein 2 (egr-2) in the frontal cortex. Mice were treated with PCP (10 mg/kg) or saline for 10 days, followed by a 5-day washout period. The PCP pretreatment increased the overall induction of HTR and frontal cortex IEG mRNA expression following a single challenge with DOI. These functional changes were not associated with changes in 5-HT2A R binding. Also, binding of the 5-HT1A R and the 5-HT transporter was unaffected. Finally, basal mRNA level of ARC was increased in the prefrontal cortex after subchronic PCP administration as revealed with in situ hybridization. Together these findings indicate that PCP administration produces changes in the brain that result in an increase in the absolute effect of DOI. Therefore, neurotransmission involving the 5-HT2A R could contribute to the behavioral deficits observed after PCP treatment. © 2013 Wiley Periodicals, Inc. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 33 | Eur Neuropsychopharmacol 2013 Nov 23: 1516-29 |
| PMID | 23357084 |
| Title | Imaging brain gene expression profiles by antipsychotics: region-specific action of amisulpride on postsynaptic density transcripts compared to haloperidol. |
| Abstract | Induction of motor disorders is considered the clinical landmark differentiating typical from atypical antipsychotics, and has been mainly correlated to dopamine D2 receptors blockade in striatum. This view is challenged by benzamides, such as amisulpride, which display low liability for motor side effects despite being D2/D3 receptors high-affinity blocking agents. These effects have been explained with the prominent presynaptic action of amisulpride or with the fast dissociation at D2 receptors, but there is scARCe information on the effects of amisulpride on postsynaptic signaling. We carried out a molecular imaging study of gene expression after acute administration of haloperidol (0.8 mg/kg), amisulpride (10 or 35 mg/kg), or vehicle, focusing on postsynaptic genes that are key regulators of synaptic plasticity, such as ARC, c-fos, Zif-268, Norbin, Homer. The last one has been associated to schizophrenia both in clinical and preclinical studies, and is differentially induced by antipsychotics with different D2 receptors affinity. Topography of gene expression revealed that amisulpride, unlike haloperidol, triggers transcripts expression peak in medial striatal regions. Correlation analysis of gene expression revealed a prevalent correlated gene induction within motor corticostriatal regions by haloperidol and a more balanced gene induction within limbic and motor corticostriatal regions by amisulpride. Despite the selective dopaminergic profile of both compounds, our results demonstrated a differential modulation of postsynaptic molecules by amisulpride and haloperidol, the former impacting preferentially medial regions of striatum whereas the latter inducing strong gene expression in lateral regions. Thus, we provided a possible molecular profile of amisulpride, putatively explaining its "atypical atypicality". |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 34 | Front Behav Neurosci 2014 -1 8: 388 |
| PMID | 25414651 |
| Title | Addiction and reward-related genes show altered expression in the postpartum nucleus accumbens. |
| Abstract | Motherhood involves a switch in natural rewards, whereby offspring become highly rewarding. Nucleus accumbens (NAC) is a key CNS region for natural rewards and addictions, but to date no study has evaluated on a large scale the events in NAC that underlie the maternal change in natural rewards. In this study we utilized microarray and bioinformatics approaches to evaluate postpartum NAC gene expression changes in mice. Modular Single-set Enrichment Test (MSET) indicated that postpartum (relative to virgin) NAC gene expression profile was significantly enriched for genes related to addiction and reward in five of five independently curated databases (e.g., Malacards, Phenopedia). Over 100 addiction/reward related genes were identified and these included: Per1, Per2, ARC, Homer2, Creb1, Grm3, Fosb, Gabrb3, Adra2a, Ntrk2, Cry1, Penk, Cartpt, Adcy1, Npy1r, Htr1a, Drd1a, Gria1, and Pdyn. ToppCluster analysis found maternal NAC expression profile to be significantly enriched for genes related to the drug action of nicotine, ketamine, and dronabinol. Pathway analysis indicated postpartum NAC as enriched for RNA processing, CNS development/differentiation, and transcriptional regulation. Weighted Gene Coexpression Network Analysis (WGCNA) identified possible networks for transcription factors, including Nr1d1, Per2, Fosb, Egr1, and Nr4a1. The postpartum state involves increased risk for mental health disorders and MSET analysis indicated postpartum NAC to be enriched for genes related to depression, bipolar disorder (BPD), and schizophrenia. Mental health related genes included: Fabp7, Grm3, Penk, and Nr1d1. We confirmed via quantitative PCR Nr1d1, Per2, Grm3, Penk, Drd1a, and Pdyn. This study indicates for the first time that postpartum NAC involves large scale gene expression alterations linked to addiction and reward. Because the postpartum state also involves decreased response to drugs, the findings could provide insights into how to mitigate addictions. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 35 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2014 Jan 48: 287-94 |
| PMID | 23085507 |
| Title | Immune system and glucose metabolism interaction in schizophrenia: a chicken-egg dilemma. |
| Abstract | Impaired glucose metabolism and the development of metabolic syndrome contribute to a reduction in the average life expectancy of individuals with schizophrenia. It is unclear whether this association simply reflects an unhealthy lifestyle or whether weight gain and impaired glucose tolerance in patients with schizophrenia are directly attributable to the side effects of atypical antipsychotic medications or disease-inherent derangements. In addition, numerous previous studies have highlighted alterations in the immune system of patients with schizophrenia. Increased concentrations of interleukin (IL)-1, IL-6, and transforming growth factor-beta (TGF-?) appear to be state markers, whereas IL-12, interferon-gamma (IFN-?), tumor necrosis factor-alpha (TNF-?), and soluble IL-2 receptor (sIL-2R) appear to be trait markers of schizophrenia. Moreover, the mononuclear phagocyte system (MPS) and microglial activation are involved in the early course of the disease. This review illustrates a "chicken-egg dilemma", as it is currently unclear whether impaired cerebral glucose utilization leads to secondary disturbances in peripheral glucose metabolism, an increased risk of cardiovascular complications, and accompanying pro-inflammatory changes in patients with schizophrenia or whether immune mechanisms may be involved in the initial pathogenesis of schizophrenia, which leads to disturbances in glucose metabolism such as metabolic syndrome. Alternatively, shared underlying factors may be responsible for the co-occurrence of immune system and glucose metabolism disturbances in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 36 | Nature 2014 Feb 506: 185-90 |
| PMID | 24463508 |
| Title | A polygenic burden of rare disruptive mutations in schizophrenia. |
| Abstract | schizophrenia is a common disease with a complex aetiology, probably involving multiple and heterogeneous genetic factors. Here, by analysing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we demonstrate a polygenic burden primarily arising from rare (less than 1 in 10,000), disruptive mutations distributed across many genes. Particularly enriched gene sets include the voltage-gated calcium ion channel and the signalling complex formed by the activity-regulated cytoskeleton-associated scaffold protein (ARC) of the postsynaptic density, sets previously implicated by genome-wide association and copy-number variation studies. Similar to reports in autism, targets of the fragile X mental retardation protein (FMRP, product of FMR1) are enriched for case mutations. No individual gene-based test achieves significance after correction for multiple testing and we do not detect any alleles of moderately low frequency (approximately 0.5 to 1 per cent) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene-mapping paradigms in neuropsychiatric disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 37 | Neurochem. Int. 2014 Sep 75: 76-8 |
| PMID | 24915645 |
| Title | Chronic D-serine reverses arc expression and partially rescues dendritic abnormalities in a mouse model of NMDA receptor hypofunction. |
| Abstract | Activity-regulated cytoskeleton-associated protein (ARC) is an immediate early gene that is expressed almost exclusively in glutamatergic neurons. ARC protein is enriched in the postsynaptic density (PSD) and colocalizes with the N-methyl-D-aspartate receptor (NMDAR) complex. ARC transcription is positively modulated by NMDAR activity and is important for dendritic spine plasticity. Genetic ablation of serine racemase (SR-/-), the enzyme that converts L-serine to D-serine, a coagonist at the NMDAR, reduces dendritic spine density in the hippocampus. Here we demonstrate that SR deficient (SR-/-) mice also have reduced ARC protein expression in the hippocampus that can be reversed with chronic D-serine administration in adulthood. Furthermore, D-serine treatment partially rescues the hippocampal spine deficit in SR-/- mice. These results demonstrate the importance of D-serine in regulating the hippocampal expression of ARC in vivo. In addition, our findings underscore the potential utility of using the glycine modulatory site agonist D-serine to treat disorders that exhibit ARC and dendritic spine dysregulation as a consequence of NMDAR hypofunction, such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 38 | Pharmacol. Res. 2014 Feb 80: 1-8 |
| PMID | 24309096 |
| Title | Repeated aripiprazole treatment regulates Bdnf, Arc and Npas4 expression under basal condition as well as after an acute swim stress in the rat brain. |
| Abstract | Despite the rapid control of schizophrenic symptoms is due to the ability of antipsychotic drugs (APDs) to block D2 receptors in the mesolimbic pathway, it is now well-established that the therapeutic effects rely on adaptive mechanisms set in motion by their long-term administration. Such neuroplastic mechanisms depend on the pharmacological profile of the drug employed, with marked differences existing between first and second generation APDs. On these bases, the major accomplishment of this work was to investigate neuroadaptive changes set in motion by repeated treatment with aripiprazole, a novel APD that is unique for being a partial agonist at dopamine D2 receptors. Moreover, given that stress plays a critical role in the exacerbation of disease symptoms, we also investigated whether aripiprazole could influence the dynamic response of the brain to an acute challenge. We found that repeated aripiprazole treatment in rats regulates the expression of different markers of neuroplasticity such as Bdnf, ARC and Npas4 in a brain-region specific fashion; more importantly, the expression of these molecules was significantly up-regulated by an acute swim stress only in aripiprazole-treated animals, which is suggestive of increased ability to cope with the adverse event. We indeed found an overall facilitation of Bdnf expression, an effect that is mainly evident in the prefrontal cortex on the pool of transcripts undergoing dendritic localization. Overall, our results provide novel information regarding the mechanisms through which aripiprazole may regulate brain function and could contribute to improve neuroplastic defects that are associated with schizophrenia symptomatology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 39 | Pharmacol. Res. 2014 Feb 80: 1-8 |
| PMID | 24309096 |
| Title | Repeated aripiprazole treatment regulates Bdnf, Arc and Npas4 expression under basal condition as well as after an acute swim stress in the rat brain. |
| Abstract | Despite the rapid control of schizophrenic symptoms is due to the ability of antipsychotic drugs (APDs) to block D2 receptors in the mesolimbic pathway, it is now well-established that the therapeutic effects rely on adaptive mechanisms set in motion by their long-term administration. Such neuroplastic mechanisms depend on the pharmacological profile of the drug employed, with marked differences existing between first and second generation APDs. On these bases, the major accomplishment of this work was to investigate neuroadaptive changes set in motion by repeated treatment with aripiprazole, a novel APD that is unique for being a partial agonist at dopamine D2 receptors. Moreover, given that stress plays a critical role in the exacerbation of disease symptoms, we also investigated whether aripiprazole could influence the dynamic response of the brain to an acute challenge. We found that repeated aripiprazole treatment in rats regulates the expression of different markers of neuroplasticity such as Bdnf, ARC and Npas4 in a brain-region specific fashion; more importantly, the expression of these molecules was significantly up-regulated by an acute swim stress only in aripiprazole-treated animals, which is suggestive of increased ability to cope with the adverse event. We indeed found an overall facilitation of Bdnf expression, an effect that is mainly evident in the prefrontal cortex on the pool of transcripts undergoing dendritic localization. Overall, our results provide novel information regarding the mechanisms through which aripiprazole may regulate brain function and could contribute to improve neuroplastic defects that are associated with schizophrenia symptomatology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 40 | Nature 2014 Feb 506: 179-84 |
| PMID | 24463507 |
| Title | De novo mutations in schizophrenia implicate synaptic networks. |
| Abstract | Inherited alleles account for most of the genetic risk for schizophrenia. However, new (de novo) mutations, in the form of large chromosomal copy number changes, occur in a small fraction of cases and disproportionally disrupt genes encoding postsynaptic proteins. Here we show that small de novo mutations, affecting one or a few nucleotides, are overrepresented among glutamatergic postsynaptic proteins comprising activity-regulated cytoskeleton-associated protein (ARC) and N-methyl-d-aspartate receptor (NMDAR) complexes. Mutations are additionally enriched in proteins that interact with these complexes to modulate synaptic strength, namely proteins regulating actin filament dynamics and those whose messenger RNAs are targets of fragile X mental retardation protein (FMRP). Genes affected by mutations in schizophrenia overlap those mutated in autism and intellectual disability, as do mutation-enriched synaptic pathways. Aligning our findings with a parallel case-control study, we demonstrate reproducible insights into aetiological mechanisms for schizophrenia and reveal pathophysiology shared with other neurodevelopmental disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 41 | Front Behav Neurosci 2014 -1 8: 75 |
| PMID | 24659959 |
| Title | MK-801 Impairs Cognitive Coordination on a Rotating Arena (Carousel) and Contextual Specificity of Hippocampal Immediate-Early Gene Expression in a Rat Model of Psychosis. |
| Abstract | Flexible behavior in dynamic, real-world environments requires more than static spatial learning and memory. Discordant and unstable cues must be organized in coherent subsets to give rise to meaningful spatial representations. We model this form of cognitive coordination on a rotating arena - Carousel where arena- and room-bound spatial cues are dissociated. Hippocampal neuronal ensemble activity can repeatedly switch between multiple representations of such an environment. Injection of tetrodotoxin into one hippocampus prevents cognitive coordination during avoidance of a stationary room-defined place on the Carousel and increases coactivity of previously unrelated neurons in the uninjected hippocampus. Place avoidance on the Carousel is impaired after systemic administration of non-competitive NMDAr blockers (MK-801) used to model schizophrenia in animals and people. We tested if this effect is due to cognitive disorganization or other effect of NMDAr antagonism such as hyperlocomotion, spatial memory impairment, or general learning deficit. We also examined if the same dose of MK-801 alters patterns of immediate-early gene (IEG) expression in the hippocampus. IEG expression is triggered in neuronal nuclei in a context-specific manner after behavioral exploration and it is used to map activity in neuronal populations. IEG expression is critical for maintenance of synaptic plasticity and memory consolidation. We show that the same dose of MK-801 that impairs spatial coordination of rats on the Carousel also eliminates contextual specificity of IEG expression in hippocampal CA1 ensembles. This effect is due to increased similarity between ensembles activated in different environments, consistent with the idea that it is caused by increased coactivity between neurons, which did not previously fire together. Our data support the proposition of the Hypersynchrony theory that cognitive disorganization in psychosis is due to increased coactivity between unrelated neurons. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 42 | Eur Neuropsychopharmacol 2014 Dec 24: 1916-24 |
| PMID | 25453483 |
| Title | Glutaminase1 heterozygous mice show enhanced trace fear conditioning and Arc/Arg3.1 expression in hippocampus and cingulate cortex. |
| Abstract | Mice heterozygous for a mutation in the glutaminase (GLS1) gene (GLS1 HZ mice), with reduced glutamate recycling and release, display reduced hippocampal function as well as memory of contextual cues in a delay fear conditioning (FC) paradigm. Here, we asked whether this deficit reflects an inability to process contextual information or a selective alteration in salience attribution. In addition, we asked whether baseline and activity-induced hippocampal activity were diminished in GLS1 HZ mice. For this purpose, we manipulated the relative salience of the conditioned stimulus (CS) and contextual cues in FC tasks, and examined gene expression of the immediate early gene ARC (ARC/Arg3.1) in hippocampus and anterior cingulate cortex (ACC) following trace FC (tFC). The results indicate that GLS1 HZ mice succeed in processing contextual information when the salient CS is absent or less predictive. In addition, in the hippocampus-dependent tFC paradigm GLS1 HZ mice display enhanced CS learning. Furthermore, while baseline ARC activation was reduced in GLS1 HZ mice in the hippocampus, in line with previous fMRI findings, it was enhanced in the hippocampus and anterior cingulate cortex following tFC. These findings suggest that GLS1 HZ mice have a pro-cognitive profile in the tFC paradigm, and this phenotype involves activation of both hippocampus and ACC. Taken together with previous work on the GLS1 HZ mouse, this study sheds light on the importance of glutamate transmission to memory processes that require the allocation of attentional resources, and extends our understanding of the underpinnings of attention deficits in SZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 43 | Mol Brain 2014 -1 7: 74 |
| PMID | 25298178 |
| Title | Behavioral characterization of mice overexpressing human dysbindin-1. |
| Abstract | The dysbindin-1 gene (DTNBP1: dystrobrevin binding protein 1) is a promising schizophrenia susceptibility gene, known to localize almost exclusively to neurons in the brain, and participates in the regulation of neurotransmitter release, membrane-surface receptor expression, and synaptic plasticity. Sandy mice, with spontaneous Dtnbp1 deletion, display behavioral abnormalities relevant to symptoms of schizophrenia. However, it remains unknown if dysbindin-1 gain-of-function is beneficial or detrimental. To answer this question and gain further insight into the pathophysiology and therapeutic potential of dysbindin-1, we developed transgenic mice expressing human DTNBP1 (Dys1A-Tg) and analyzed their behavioral phenotypes. Dys1A-Tg mice were born viable in the expected Mendelian ratios, apparently normal and fertile. Primary screening of behavior and function showed a marginal change in limb grasping in Dys1A-Tg mice. In addition, Dys1A-Tg mice exhibited increased hyperlocomotion after methamphetamine injection. Transcriptomic analysis identified several up- and down-regulated genes, including the immediate-early genes ARC and Egr2, in the prefrontal cortex of Dys1A-Tg mice. The present findings in Dys1A-Tg mice support the role of dysbindin-1 in psychiatric disorders. The fact that either overexpression (Dys1A-Tg) or underexpression (Sandy) of dysbindin-1 leads to behavioral alterations in mice highlights the functional importance of dysbindin-1 in vivo. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 44 | Neuron 2015 Apr 86: 490-500 |
| PMID | 25864631 |
| Title | Structural basis of arc binding to synaptic proteins: implications for cognitive disease. |
| Abstract | ARC is a cellular immediate-early gene (IEG) that functions at excitatory synapses and is required for learning and memory. We report crystal structures of ARC subdomains that form a bi-lobar ARChitecture remarkably similar to the capsid domain of human immunodeficiency virus (HIV) gag protein. Analysis indicates ARC originated from the Ty3/Gypsy retrotransposon family and was "domesticated" in higher vertebrates for synaptic functions. The ARC N-terminal lobe evolved a unique hydrophobic pocket that mediates intermolecular binding with synaptic proteins as resolved in complexes with TARP?2 (Stargazin) and CaMKII peptides and is essential for ARC's synaptic function. A consensus sequence for ARC binding identifies several additional partners that include genes implicated in schizophrenia. ARC N-lobe binding is inhibited by small chemicals suggesting ARC's synaptic action may be druggable. These studies reveal the remarkable evolutionary origin of ARC and provide a structural basis for understanding ARC's contribution to neural plasticity and disease. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 45 | PLoS ONE 2015 -1 10: e0135076 |
| PMID | 26474411 |
| Title | Association of SNPs in EGR3 and ARC with Schizophrenia Supports a Biological Pathway for Schizophrenia Risk. |
| Abstract | We have previously hypothesized a biological pathway of activity-dependent synaptic plasticity proteins that addresses the dual genetic and environmental contributions to schizophrenia. Accordingly, variations in the immediate early gene EGR3, and its target ARC, should influence schizophrenia susceptibility. We used a pooled Next-Generation Sequencing approach to identify variants across these genes in U.S. populations of European (EU) and African (AA) descent. Three EGR3 and one ARC SNP were selected and genotyped for validation, and three SNPs were tested for association in a replication cohort. In the EU group of 386 schizophrenia cases and 150 controls EGR3 SNP rs1877670 and ARC SNP rs35900184 showed significant associations (p = 0.0078 and p = 0.0275, respectively). In the AA group of 185 cases and 50 controls, only the ARC SNP revealed significant association (p = 0.0448). The ARC SNP did not show association in the Han Chinese (CH) population. However, combining the EU, AA, and CH groups revealed a highly significant association of ARC SNP rs35900184 (p = 2.353 x 10(-7); OR [95% CI] = 1.54 [1.310-1.820]). These findings support previously reported associations between EGR3 and schizophrenia. Moreover, this is the first report associating an ARC SNP with schizophrenia and supports recent large-scale GWAS findings implicating the ARC complex in schizophrenia risk. These results support the need for further investigation of the proposed pathway of environmentally responsive, synaptic plasticity-related, schizophrenia genes. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 46 | Neuropharmacology 2015 Dec 99: 256-63 |
| PMID | 26044638 |
| Title | The PDE10A inhibitor MP-10 and haloperidol produce distinct gene expression profiles in the striatum and influence cataleptic behavior in rodents. |
| Abstract | Phosphodiesterase 10A (PDE10A) has garnered attention as a potential therapeutic target for schizophrenia due to its prominent striatal expression and ability to modulate striatal signaling. The present study used the selective PDE10A inhibitor MP-10 and the dopamine D2 antagonist haloperidol to compare effects of PDE10A inhibition and dopamine D2 blockade on striatopallidal (D2) and striatonigral (D1) pathway activation. Our studies confirmed that administration of MP-10 significantly elevates expression of the immediate early genes (IEG) c-fos, egr-1, and ARC in rat striatum. Furthermore, we demonstrated that MP-10 induced egr-1 expression was distributed evenly between enkephalin-containing D2-neurons and substance P-containing D1-neurons. In contrast, haloperidol (3 mg/kg) selectively activated egr-1 expression in enkephalin neurons. Co-administration of MP-10 and haloperidol (0.5 mg/kg) increased IEG expression to a greater extent than either compound alone. Similarly, in a rat catalepsy assay, administration of haloperidol (0.5 mg/kg) or MP-10 (3-30 mg/kg) did not produce cataleptic behavior when dosed alone, but co-administration of haloperidol with MP-10 (3 and 10 mg/kg) induced cataleptic behaviors. Interestingly, co-administration of haloperidol with a high dose of MP-10 (30 mg/kg) failed to produce cataleptic behavior. These findings are important for understanding the neural circuits involved in catalepsy and suggest that the behavioral effects produced by PDE10A inhibitors may be influenced by concomitant medication and the level of PDE10A inhibition achieved by the dose of the inhibitor. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 47 | Eur Neuropsychopharmacol 2015 Apr 25: 566-82 |
| PMID | 25649681 |
| Title | Progressive recruitment of cortical and striatal regions by inducible postsynaptic density transcripts after increasing doses of antipsychotics with different receptor profiles: insights for psychosis treatment. |
| Abstract | Antipsychotics may modulate the transcription of multiple gene programs, including those belonging to postsynaptic density (PSD) network, within cortical and subcortical brain regions. Understanding which brain region is activated progressively by increasing doses of antipsychotics and how their different receptor profiles may impact such an activation could be relevant to better correlate the mechanism of action of antipsychotics both with their efficacy and side effects. We analyzed the differential topography of PSD transcripts by incremental doses of two antipsychotics: haloperidol, the prototypical first generation antipsychotic with prevalent dopamine D2 receptors antagonism, and asenapine, a second generation antipsychotic characterized by multiple receptors occupancy. We investigated the expression of PSD genes involved in synaptic plasticity and previously demonstrated to be modulated by antipsychotics: Homer1a, and its related interacting constitutive genes Homer1b/c and PSD95, as well as ARC, C-fos and Zif-268, also known to be induced by antipsychotics administration. We found that increasing acute doses of haloperidol induced immediate-early genes (IEGs) expression in different striatal areas, which were progressively recruited by incremental doses with a dorsal-to-ventral gradient of expression. Conversely, increasing acute asenapine doses progressively de-recruited IEGs expression in cortical areas and increased striatal genes signal intensity. These effects were mirrored by a progressive reduction in locomotor animal activity by haloperidol, and an opposite increase by asenapine. Thus, we demonstrated for the first time that antipsychotics may progressively recruit PSD-related IEGs expression in cortical and subcortical areas when administered at incremental doses and these effects may reflect a fine-tuned dose-dependent modulation of the PSD. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 48 | Schizophr. Res. 2015 Mar 162: 216-21 |
| PMID | 25592804 |
| Title | Subchronic pharmacological and chronic genetic NMDA receptor hypofunction differentially regulate the Akt signaling pathway and Arc expression in juvenile and adult mice. |
| Abstract | NMDA receptor (NMDAR) hypofunction is a compelling hypothesis for the pathophysiology of schizophrenia, because in part, NMDAR antagonists cause symptoms in healthy adult subjects that resemble schizophrenia. Therefore, NMDAR antagonists have been used as a method to induce NMDAR hypofunction in animals as a pharmacological model of schizophrenia. Serine racemase-null mutant (SR-/-) mice display constitutive NMDAR hypofunction due to the lack of d-serine. SR-/- mice have deficits in tropomyosin-related kinase receptor (TrkB)/Akt signaling and activity regulated cytoskeletal protein (ARC) expression, which mirror what is observed in schizophrenia. Thus, we analyzed these signaling pathways in MK801 sub-chronically (0.15mg/kg; 5days) treated adult wild-type mice. We found that in contrast to SR-/- mice, the activated states of downstream signaling molecules, but not TrkB, increased in MK801 treated mice. Furthermore, there is an age-dependent change in the behavioral reaction of people to NMDAR antagonists. We therefore administered the same dosing regimen of MK801 to juvenile mice and compared them to juvenile SR-/- mice. Our findings demonstrate that pharmacological NMDAR antagonism has different effects on TrkB/Akt signaling than genetically-induced NMDAR hypofunction. Given the phenotypic disparity between the MK801 model and schizophrenia, our results suggest that SR-/- mice more accurately reflect NMDAR hypofunction in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 49 | Front Behav Neurosci 2015 -1 9: 117 |
| PMID | 26042007 |
| Title | Altered neuronal excitability underlies impaired hippocampal function in an animal model of psychosis. |
| Abstract | Psychosis is accompanied by severe attentional deficits, and impairments in associational-memory processing and sensory information processing that are ascribed to dysfunctions in prefrontal and hippocampal function. Disruptions of glutamatergic signaling may underlie these alterations: Antagonism of the N-methyl-D-aspartate receptor (NMDAR) results in similar molecular, cellular, cognitive and behavioral changes in rodents and/or humans as those that occur in psychosis, raising the question as to whether changes in glutamatergic transmission may be intrinsic to the pathophysiology of the disease. In an animal model of psychosis that comprises treatment with the irreversible NMDAR-antagonist, MK801, we explored the cellular mechanisms that may underlie hippocampal dysfunction in psychosis. MK801-treatment resulted in a profound loss of hippocampal LTP that was evident 4 weeks after treatment. Whereas neuronal expression of the immediate early gene, ARC, was enhanced in the hippocampus by spatial learning in controls, MK801-treated animals failed to show activity-dependent increases in ARC expression. By contrast, a significant increase in basal ARC expression in the absence of learning was evident compared to controls. Paired-pulse (PP) facilitation was increased at the 40 ms interval indicating that NMDAR and/or fast GABAergic-mediated neurotransmission was disrupted. In line with this, MK801-treatment resulted in a significant decrease in GABA(A), and increase in GABA(B)-receptor-expression in PFC, along with a significant increase of GABA(B)- and NMDAR-GluN2B expression in the dentate gyrus. NMDAR-GluN1 or GluN2A subunit expression was unchanged. These data suggest that in psychosis, deficits in hippocampus-dependent memory may be caused by a loss of hippocampal LTP that arises through enhanced hippocampal neuronal excitability, altered GluN2B and GABA receptor expression and an uncoupling of the hippocampus-prefrontal cortex circuitry. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 50 | Biol. Psychiatry 2015 Jan 77: 52-8 |
| PMID | 25152434 |
| Title | Genetic risk for schizophrenia: convergence on synaptic pathways involved in plasticity. |
| Abstract | Recent large-scale genomic studies have revealed two broad classes of risk alleles for schizophrenia: a polygenic component of risk mediated through multiple common risk variants and rarer more highly penetrant submicroscopic chromosomal deletions and duplications, known as copy number variants. The focus of this review is on the emerging findings from the latter and subsequent exome sequencing data of smaller, deleterious single nucleotide variants and indels. In these studies, schizophrenia patients were found to have enriched de novo mutations in genes belonging to the postsynaptic density at glutamatergic synapses, particularly components of the N-methyl-D-aspartate receptor signaling complex, including the PSD-95 complex, activity-regulated cytoskeleton-associated protein interactors, the fragile X mental retardation protein complex, voltage-gated calcium channels, and genes implicated in actin cytoskeletal dynamics. The convergence of these implicated genes onto a coherent biological pathway at the synapse, with a specific role in plasticity, provides a significant advance in understanding pathogenesis and points to new targets for biological investigation. We consider the implications of these studies in the context of existing genetic data and the potential need to reassess diagnostic boundaries of neuropsychiatric disorders before discussing ways forward for more directed mechanistic studies to develop stratified, novel therapeutic approaches in the future. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 51 | JAMA Psychiatry 2015 Aug 72: 747-56 |
| PMID | 26038830 |
| Title | Altered Markers of Cortical ?-Aminobutyric Acid Neuronal Activity in Schizophrenia: Role of the NARP Gene. |
| Abstract | In schizophrenia, working memory deficits appear to reflect abnormalities in the generation of gamma oscillations in the dorsolateral prefrontal cortex. The generation of gamma oscillations requires the phasic excitation of inhibitory parvalbumin-containing interneurons. Thus, gamma oscillations depend, in part, on the number of synaptic glutamate receptors on parvalbumin interneurons. However, little is known about the molecular factors that regulate glutamate receptor-mediated excitation of parvalbumin interneurons in schizophrenia. To quantify in individuals with schizophrenia the expression of immediate early genes (NARP, ARC, and SGK1) regulating glutamate synaptic neurotransmission. Postmortem brain specimens (n?=?206) were obtained from individuals with schizophrenia, bipolar disorder, or major depressive disorder and from well-matched healthy persons (controls). For a study of brain tissue, quantitative polymerase chain reaction, in situ hybridization, or microarray analyses were used to measure transcript levels in the dorsolateral prefrontal cortex at gray matter, laminar, and cellular levels of resolutions. This study was conducted between January 1, 2013, and November 30, 2014. Expression levels for NARP, ARC, and SGK1 messenger RNA (mRNA) were compared between specimens from individuals with schizophrenia and controls. Diagnostic specificity was assessed by quantifying NARP mRNA levels in specimens from individuals with mood disorders. By quantitative polymerase chain reaction, levels of NARP mRNA were significantly lower by 25.6% in specimens from individuals with schizophrenia compared with the controls (mean [SD], 0.036 [0.018] vs 0.049 [0.015]; F1,114?=?21.0; P?ARC (F1,112?=?0.93; P?=?.34) and SGK1 (F1,110?=?2.52; P?=?.12) were not significant. These findings were supported by in situ hybridization (NARP; individuals with schizophrenia vs controls: 40.1% lower [P?=?.003]) and microarray analyses (NARP; individuals with schizophrenia vs controls: 12.2% lower in layer 3 [P?=?.11] and 14.6% lower in layer 5 pyramidal cells [P?=?.001]). In schizophrenia specimens, NARP mRNA levels were positively correlated with GAD67 mRNA (r?=?0.55; P?Given the role of NARP in the formation of excitatory inputs to parvalbumin (and perhaps somatostatin) interneurons, our findings suggest that lower NARP mRNA expression contributes to lower excitatory drive onto parvalbumin interneurons in schizophrenia. This reduced excitatory drive may lead to lower synthesis of ?-aminobutyric acid in these interneurons, contributing to a reduced capacity to generate the gamma oscillations required for working memory. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 52 | Mol. Neurobiol. 2016 Feb -1: -1 |
| PMID | 26873854 |
| Title | Neuronal Activity-Induced Sterol Regulatory Element Binding Protein-1 (SREBP1) is Disrupted in Dysbindin-Null Mice-Potential Link to Cognitive Impairment in Schizophrenia. |
| Abstract | schizophrenia is a chronic debilitating neuropsychiatric disorder that affects about 1 % of the population. Dystrobrevin-binding protein 1 (DTNBP1 or dysbindin) is one of the ReseARCh Domain Constructs (RDoC) associated with cognition and is significantly reduced in the brain of schizophrenia patients. To further understand the molecular underpinnings of pathogenesis of schizophrenia, we have performed microarray analyses of the hippocampi from dysbindin knockout mice, and found that genes involved in the lipogenic pathway are suppressed. Moreover, we discovered that maturation of a master transcriptional regulator for lipid synthesis, sterol regulatory element binding protein-1 (SREBP1) is induced by neuronal activity, and is required for induction of the immediate early gene ARC (activity-regulated cytoskeleton-associated protein), necessary for synaptic plasticity and memory. We found that nuclear SREBP1 is dramatically reduced in dysbindin-1 knockout mice and postmortem brain tissues from human patients with schizophrenia. Furthermore, activity-dependent maturation of SREBP1 as well as ARC expression were attenuated in dysbindin-1 knockout mice, and these deficits were restored by an atypical antipsychotic drug, clozapine. Together, results indicate an important role of dysbindin-1 in neuronal activity induced SREBP1 and ARC, which could be related to cognitive deficits in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |
| 53 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2016 May 70: 24-38 |
| PMID | 27177972 |
| Title | Switching antipsychotics: Imaging the differential effect on the topography of postsynaptic density transcripts in antipsychotic-naïve vs. antipsychotic-exposed rats. |
| Abstract | The postsynaptic density (PSD) has been regarded as a functional switchboard at the crossroads of a dopamine-glutamate interaction, and it is putatively involved in the pathophysiology of psychosis. Indeed, it has been demonstrated that antipsychotics may modulate several PSD transcripts, such as PSD-95, Shank, and Homer. Despite switching antipsychotics is a frequent strategy to counteract lack of efficacy and/or side effect onset in clinical practice, no information is available on the effects of sequential treatments with different antipsychotics on PSD molecules. The aim of this study was to evaluate whether a previous exposure to a typical antipsychotic and a switch to an atypical one may affect the expression of PSD transcripts, in order to evaluate potential neurobiological correlates of this common clinical practice, with specific regards to putative synaptic plasticity processes. We treated male Sprague-Dawley rats intraperitoneally for 15days with haloperidol or vehicle, then from the sixteenth day we switched the animals to amisulpride or continued to treat them with vehicle or haloperidol for 15 additional days. In this way we got six first treatment/second treatment groups: vehicle/vehicle, vehicle/haloperidol, vehicle/amisulpride, haloperidol/vehicle, haloperidol/haloperidol, haloperidol/amisulpride. In this paradigm, we evaluated the expression of brain transcripts belonging to relevant and interacting PSD proteins, both of the Immediate-Early Gene (Homer1a, ARC) and the constitutive classes (Homer1b/c and PSD-95). The major finding was the differential effect of amisulpride on gene transcripts when administered in naïve vs. antipsychotic-pretreated rats, with modifications of the ratio between Homer1a/Homer1b transcripts and differential effects in cortex and striatum. These results suggest that the neurobiological effects on PSD transcripts of amisulpride, and possibly of other antipsychotics, may be greatly affected by prior antipsychotic treatments and may impact significantly on the switching procedure. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics, schizophrenias |