UMLS:C0036341 - FACTA Search

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Query: UMLS:C0036341 (schizophrenia)
60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Typical and atypical antipsychotics, the mainstay of schizophrenia pharmacotherapy, have been demonstrated to affect differently neuronal gene expression in several preclinical paradigms. Here we report the differential gene expression of the glutamatergic post-synaptic density proteins Homer and PSD-95 in rat forebrain following acute haloperidol or olanzapine treatment. Moreover, considering the extensive interactions between dopaminergic and opioidergic systems we also measured striatal preproenkephalin mRNA. Male Sprague-Dawley rats were treated with haloperidol 1 mg/kg or olanzapine 0.5 mg/kg or vehicle, i.p. and sacrificed 3 h after the injection. Homer gene expression was significantly increased in caudate putamen and nucleus accumbens of rats treated with haloperidol and in the core of accumbens of rats treated with olanzapine. No changes were detected for Homer in prefrontal and parietal cortex in any of the experimental groups. PSD-95 gene expression was not modulated in our paradigm by administration of either typical or atypical antipsychotics. These results (1) suggest a differential modulation of Homer by typical and atypical antipsychotics; (2) confirm that Homer can be induced as an early gene with putative direct effect on neuronal plasticity and (3) demonstrate different response to antipsychotics by different classes of postsynaptic density proteins at glutamatergic synapses.
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PMID:Acute administration of antipsychotics modulates Homer striatal gene expression differentially. 1183 3

Schizophrenia has been associated with dysfunction of glutamatergic neurotransmission. Synaptic glutamate activates pre- and postsynaptic ionotropic NMDA, AMPA, and kainate and metabotropic receptors, is removed from the synapse via five cell surface-expressed transporters, and is packaged for release by three vesicular transporters. In addition, there is a family of intracellular molecules enriched in the postsynaptic density (PSD) that target glutamate receptors to the synaptic membrane, modulate receptor activity, and coordinate glutamate receptor-related signal transduction. Each family of PSD proteins is selective for a given glutamate receptor subtype, the most well characterized being the NMDA receptor binding proteins PSD93, PSD95, NF-L, and SAP102. Besides binding glutamate receptors, many of these proteins also interact with cell surface proteins like cell adhesion molecules, ion channels, cytoskeletal elements, and signal transduction molecules. Given the complexity of the glutamate neurotransmitter system, there are many locations where disruption of normal signaling could occur and give rise to abnormal glutamatergic neurotransmission in schizophrenia. Using multiple cohorts of postmortem tissue, we have examined these synaptic molecules in schizophrenic thalamus. The expression of NR1 and NR2C subunit transcripts is decreased in the thalamus in schizophrenia. Interestingly, three intracellular PSD molecules that link the NMDA receptor to signal transduction pathways are also abnormally expressed. Additionally, several of the cell surface and vesicular transporters are abnormal in the schizophrenic thalamus. While occasional findings of abnormal receptor expression are made, the most dramatic and consistent alterations that we have found in the thalamus in schizophrenia involve the family of intracellular signaling/scaffolding molecules. We propose that schizophrenia has a glutamatergic component that involves alterations in the intracellular machinery that is coupled to glutamate receptors, in addition to abnormalities of the receptors themselves. Our data suggest that schizophrenia is associated with abnormal glutamate receptor-related intracellular signaling in the thalamus, and point to novel targets for innovative drug discovery.
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PMID:Molecular abnormalities of the glutamate synapse in the thalamus in schizophrenia. 1468 36

Multiple neurotransmitter systems have been implicated in the pathophysiology of schizophrenia. Dopamine hyperactivity has often been implicated in this illness. More recently, the glutamate hypothesis of schizophrenia suggests that NMDA receptor (NMDAR) hypofunction may also play a role in this illness. This is based primarily on studies showing that phencyclidine, an NMDAR antagonist, can induce a schizophreniform psychosis. While NMDAR dysfunction is most often implicated in schizophrenia, other components of the glutamate system, such as the AMPA and kainate receptors, as well as NMDAR-associated intracellular proteins, may also play a role in regulating NMDA receptor activity and glutamate neurotransmission. There is growing interest in the hypothesis that the pathophysiology of schizophrenia involves alterations in dopamine-glutamate interactions. The glutamate system is anatomically and functionally linked to the dopamine system, and glutamate can modulate dopaminergic activity and release by stimulating various glutamate receptor subtypes expressed by dopaminergic neurons in the substantia nigra/ventral tegmental area. In this study, we investigated dopamine-glutamate interactions by measuring the expression of transcripts encoding the subunits for the ionotropic glutamate receptors (NMDA, AMPA and kainate) and five NMDAR-associated intracellular proteins, PSD-93, PSD-95, SAP102, NF-L and yotiao in the dopaminergic neurons in the substantia nigra pars compacta (SNc) of subjects with schizophrenia and a comparison group. Tyrosine hydroxylase (TH, a marker of dopamine-synthesizing cells), NR1 (an NMDA receptor subunit) and GluR5 (a kainate subunit) transcript levels were significantly increased in the SNc in schizophrenia. These data support the hypothesis that schizophrenia may involve alterations in dopamine-glutamate interactions.
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PMID:Expression of the ionotropic glutamate receptor subunits and NMDA receptor-associated intracellular proteins in the substantia nigra in schizophrenia. 1496 37

Several lines of investigation support a hypothesis of glutamatergic dysfunction in schizophrenia, including our recent reports of altered NMDA receptor subunit and associated intracellular protein transcripts in the thalamus of elderly patients with schizophrenia. In the present study, we used in situ hybridization to measure the expression of NMDA subunits (NR1, NR2A-D), and associated intracellular proteins (NF-L, PSD95, and SAP102) in a second, younger cohort from the Stanley Foundation Neuropathology Consortium, which included patients with both schizophrenia and affective disorders. We wanted to determine whether glutamatergic abnormalities in the thalamus in schizophrenia are present at younger ages, and whether these abnormalities occur in other psychiatric illnesses. In the present work, we observed increased expression of NMDA NR2B subunit transcripts, and decreased expression of all three associated postsynaptic density protein transcripts in schizophrenia. We also found evidence of glutamatergic dysfunction in the thalamus in affective disorders, particularly in bipolar disorder. In particular, we found decreased NF-L, PSD95, and SAP102 transcripts in bipolar disorder, and decreased SAP102 levels in major depression. Interestingly, one of the most consistent findings across diagnostic groups was an abnormality of intracellular signaling molecules that are linked to the NMDA receptor, rather than changes in the receptor subunits themselves. PSD95 and similar scaffolding molecules link the NMDA receptor with intracellular enzymes that mediate signaling, and also provide a physical link between different neurotransmitter systems to coordinate and integrate information from multiple effector systems. Abnormalities of PSD95-like molecules and other intracellular signaling machinery may contribute to dysregulated communication between multiple neurotransmitter systems (such as glutamatergic and dopaminergic systems) that are potentially involved in the neurobiology of schizophrenia and affective disorders.
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PMID:Abnormalities of the NMDA Receptor and Associated Intracellular Molecules in the Thalamus in Schizophrenia and Bipolar Disorder. 1505 76

Both the long and short arms of chromosome 18 have been consistently identified as potential locations for schizophrenia and bipolar affective disorder susceptibility genes. We previously described the identification of two independent pericentric inversions of chromosome 18 [inv(18)(p11.31;q21.2) and inv(18)(p11.31;q21.1)] occurring in two small families in which carriers have been diagnosed with schizophrenia and bipolar affective disorder, respectively. Using fluorescence in situ hybridization on patient metaphase chromosomes we have identified the locations of all four chromosome breakpoints in the inversion carriers. Neither pericentric inversion results in a direct gene disruption. However, each inversion breakpoint has the potential to perturb local gene expression by position effect or by the separation of important regulatory (enhancer) sequences from the core gene sequences. Five genes in the localities of the breakpoints have been identified as good candidates for the genetic basis of psychiatric illness in these families; TTMA, a novel membrane spanning protein; TCF4, a basic helix-loop-helix transcription factor; DLGAP1, an interactor of the PSD-95 synaptic protein; and ARKL1 and ARKL2, novel members of the ubiquitin ligase gene family.
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PMID:Candidate psychiatric illness genes identified in patients with pericentric inversions of chromosome 18. 1572 56

Previous studies have described abnormal expression of molecules involved in glutamatergic signaling in psychiatric illnesses, including proteins associated with receptor signaling complexes in the postsynaptic density (PSD). In particular the N-methyl-d-aspartate (NMDA) receptor complex has been associated with these illnesses. Several subcortical structures including the striatum are innervated by direct glutamatergic projections from the prefrontal cortex, and these connections may be affected in severe psychiatric illnesses. Abnormal expression of molecules critical for glutamatergic signaling in subcortical structures may thus be associated with the pathophysiology of severe psychiatric illnesses. In the present study postmortem tissue from patients with schizophrenia, bipolar disorder and major depression was used to examine striatal expression of transcripts encoding NMDA receptor interacting proteins of the PSD required for trafficking, membrane targeting and synaptic function of this receptor. We found decreased striatal expression of transcripts encoding PSD-95 and SAP-102 in bipolar disorder and of SAP-102 in major depression and schizophrenia, while no significant changes in NF--L and PSD-93 mRNAs were observed. Abnormal expression of SAP-102 in schizophrenia and SAP-102 and PSD-95 in mood disorders in subcortical structures receiving afferent glutamatergic innervation from frontal cortex suggests dysregulation of cortical-subcortical circuitry in these illnesses.
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PMID:Abnormal striatal expression of transcripts encoding NMDA interacting PSD proteins in schizophrenia, bipolar disorder and major depression. 1602 28

Much interest has focussed on glutamate and the N-Methyl-D-Aspartate (NMDA) glutamate receptor in the pathogenesis of schizophrenia. A number of studies have reported abnormal gene transcription of various glutamate receptor subtypes in the hippocampus including the NMDA receptor. However, corresponding protein levels in subregions of the hippocampus have not yet been investigated. We have used immunoautoradiographical techniques to assess the expression of the obligatory NMDA receptor subunit NR1 and an associated post-synaptic density protein PSD-95 in the hippocampal dentate gyrus and orbitofrontal cortex (OFC) in schizophrenia and mood disorder. Optical density measures from film autoradiographs revealed no changes in NR1 or PSD-95 in the OFC or dentate hilus, however a decrease in PSD-95 was found in the dentate molecular layer in both schizophrenia and bipolar disorder relative to major depression. These findings were unrelated to antipsychotic or mood stabilizer drug treatment. The dentate molecular layer contains the dendritic trees of granule cells and is the target of major excitatory afferent inputs from associative cortical, parahippocampal and hippocampal regions. A reduction in PSD-95 at glutamate synapses of the molecular layer may have a deleterious impact on information flow to other hippocampal regions via granule cells and their projecting mossy fibres. A down-regulation of PSD-95 in schizophrenia and bipolar disorder may also relate to disease mechanisms of psychosis.
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PMID:NMDA receptor subunit NRI and postsynaptic protein PSD-95 in hippocampus and orbitofrontal cortex in schizophrenia and mood disorder. 1614 May 6

Abnormal expression of the N-methyl-D-Aspartate (NMDA) receptor and its interacting molecules of the postsynaptic density (PSD) are thought to be involved in the pathophysiology of schizophrenia. Frontal regions of neocortex including dorsolateral prefrontal (DLPFC) and anterior cingulate cortex (ACC) are essential for cognitive and behavioral functions that are affected in schizophrenia. In this study, we have measured protein expression of two alternatively spliced isoforms of the NR1 subunit (NR1C2 and NR1C2') as well as expression of the NR2A-D subunits of the NMDA receptor in DLPFC and ACC in post-mortem samples from elderly schizophrenic patients and a comparison group. We found significantly increased expression of NR1C2' but not of NR1C2 in ACC, suggesting altered NMDA receptor cell membrane expression in this cortical area. We did not find significant changes in the expression of either of the NR1 isoforms in DLPFC. We did not detect changes of any of the NR2 subunits studied in either cortical area. In addition, we studied expression of the NMDA-interacting PSD molecules NF-L, SAP102, PSD-95 and PSD-93 in ACC and DLPFC at both transcriptional and translational levels. We found significant changes in the expression of NF-L in DLPFC, and PSD-95 and PSD-93 in ACC; increased transcript expression was associated with decreased protein expression, suggesting abnormal translation and/or accelerated protein degradation of these molecules in schizophrenia. Our findings suggest abnormal regional processing of the NMDA receptor and its associated PSD molecules, possibly involving transcription, translation, trafficking and protein stability in cortical areas in schizophrenia.
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PMID:Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia. 1670 73

Glutamate receptors of the N-methyl-D-asparate (NMDA-) subtype are tetrameric allosteric and ligand-gated calcium channels. They are modulated by a variety of endogenous ligands and ions and play a pivotal role in memory-related signal transduction due to a voltage-dependent block by magnesium, which makes them Hebbian coincidence detectors. On the structural level NMDA receptors have an enormous flexibility due to seven genes (NR1, NR2A-D and NR3A-B), alternative splicing, RNA-editing and extensive posttranslational modifications, like phosphorylation and glycosylation. NMDA receptors are thought to be responsible for excitotoxicity and subsequent downstream events like neuroinflammation and apoptosis and thus have been implicated in many important human pathologies, ranging from amyotrophic lateral sclerosis, Alzheimer's and Parkinson' disease, depression, epilepsy, trauma and stroke to schizophrenia. This fundamental significance of NMDA receptor-related excitotoxicity is discussed in the context of the developing clinical success of Memantine, but moreover set into relation to various proteomic and genetic markers of said diseases. The very complex localisational and functional regulation of NMDA receptors appears to be dependent on neuregulins and receptor tyrosine kinases in cholesterol-rich membrane domains (lipid rafts), calcium-related mitochondrial feedback-loops and subsynaptic structural elements like PSD-95 (post-synaptic density protein of 95 kD). The flexibility and multitude of interaction partners and possibilities of these highly dynamic molecular systems are discussed in terms of drug development strategies, in particular comparing high affinity and sub-type specific ligands to currently successful or promising therapies.
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PMID:NMDA receptors are not alone: dynamic regulation of NMDA receptor structure and function by neuregulins and transient cholesterol-rich membrane domains leads to disease-specific nuances of glutamate-signalling. 1671 8

Numerous studies have described structural and functional abnormalities of the thalamus in schizophrenia, but surprisingly few studies have examined neurochemical abnormalities that accompany these pathological changes. We previously identified abnormalities of multiple molecules associated with glutamatergic neurotransmission, including changes in NMDA receptor subunit transcripts and binding sites and NMDA receptor-associated post-synaptic density (PSD) protein transcripts in the thalamus of elderly patients with schizophrenia. In the present study, we performed western blot analysis to determine whether protein levels of NMDA receptor subunits (NR1, NR2A, NR2B) and associated PSD proteins (NF-L, PSD95, SAP102) are altered in schizophrenia. Thalamic tissue from each subject was grossly dissected into two regions: a dorsomedial region containing limbic-associated dorsomedial, anterior and central medial thalamic nuclei; and a ventral thalamus region that primarily consisted of the ventral lateral nucleus. We observed increased protein expression of the NR2B NMDA receptor subunit and its associated intracellular protein, PSD95, in the dorsomedial thalamus of patients with schizophrenia, but the other molecules were unchanged, and we found no changes in the ventral thalamus. These data provide additional evidence of thalamic neurochemical abnormalities, particularly in thalamic nuclei which project to limbic regions of the brain. Further, these findings provide additional evidence of NMDA receptor alterations in schizophrenia, which may play an important role in the neurobiology of the illness.
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PMID:Up-regulation of NMDA receptor subunit and post-synaptic density protein expression in the thalamus of elderly patients with schizophrenia. 1676 23

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