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)

Synaptic pathology is central in the pathogenesis of several psychiatric disorders, for example in Alzheimer's disease (AD) and schizophrenia. Quantification of specific synaptic proteins has proved to be a useful method to estimate synapitc density in the brain. Using this approach, several synaptic proteins have been demonstrated to be altered in both AD and schizophrenia. Until recently, the analysis of synaptic pathology has been limited to postmortem tissue. In living subjects, these synaptic proteins may be studied through analysis of cerebrospinal fluid (CSF). In an earlier study performed by us, one synaptic vesicle specific protein, synaptotagmin, was detected in CSF for the first time using a procedure based on affinity chromatography, reversed-phase chromatography, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and chemiluminescence immunoblotting. However, other synaptic proteins were not detectable with this procedure. Therefore, we have developed a procedure including precipitation of CSF proteins with trichloroacetic acid, followed by liquid-phase isoelectric focusing using the Rotofor Cell, and finally analysis of Rotofor fractions by Western blotting for identification of synaptic proteins in CSF. Five synaptic proteins, rab3a, synaptotagmin, growth-associated protein (GAP-43), synaptosomal-associated protein (SNAP-25) and neurogranin, have been demonstrated in CSF using this method. The major advantage of liquid-phase isoelectric focusing (IEF) using the Rotofor cell is that it provides synaptic proteins from CSF in sufficient quantities for identification. This method may also be suitable for identification of other types of trace amounts of brain-specific proteins in CSF. These results demonstrate that several synaptic proteins can be identified and measured in CSF to study synaptic function and pathology in degenerative disorders.
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PMID:Identification of synaptic vesicle, pre- and postsynaptic proteins in human cerebrospinal fluid using liquid-phase isoelectric focusing. 1021 48

Calcineurin (CaN), also designated as protein phosphatase 2B, is a major Ca2+/calmodulin-binding protein in the brain and the only serine/threonine phosphatase under the control of Ca2+/calmodulin. CaN activity has been implicated in downstream regulation of dopaminergic signal transduction and in NMDA receptor-dependent synaptic plasticity. Thus, it serves as a point of convergence for the abnormalities of these two neurotransmitter systems in schizophrenia. The aim of the present study was to determine if levels of CaN were altered in two schizophrenia- and CaN-related brain regions--the dorsolateral prefrontal cortex and hippocampus from subjects with schizophrenia compared to that in tissue from age and sex matched controls. CaN protein levels were measured by Western-blot analysis in samples from 15 schizophrenia patients vs. 15 control subjects. No significant differences in CaN protein levels were found either in the prefrontal cortex or in the hippocampus of schizophrenia patients compared to matched control subjects. Our result of lack of difference does not support the concept that brain CaN levels are a pathophysiological factor in this disorder. Further studies with antibodies against specific CaN catalytic subunit isoforms (presently unavailable) are required to resolve this issue.
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PMID:Postmortem brain calcineurin protein levels in schizophrenia patients are not different from controls. 1646 Sep 15

Schizophrenia is a complex and poorly understood neuropsychiatric disorder. Much research has begun to implicate the prefrontal cortex in the disease. Using immunocytochemistry we determined if neurogranin, a protein found in dendrites, spines and cell bodies and an upstream regulator of calcium was altered in areas 9 and 32 of schizophrenic prefrontal cortex. We examined its expression in pyramidal cells in layers III and V. Tissues from 7 controls and 7 schizophrenics (from our original MAP2 study, Jones, L., Johnson, N., Byne, W., 2002. Alterations in MAP2 staining in area 9 and 32 of schizophrenic prefrontal cortex. Psych. Res. 114, 137-148) matched for age, sex and postmortem interval were examined. Using area fraction analysis we quantified the immunostaining. Additionally, we counted the number of positively stained pyramidal cells in the same 7 pairs. Neurogranin immunostaining was dramatically reduced in both layers III (72%) and V (50%) in area 9. In area 32 there was a more modest reduction in both layers III (36%) and V (40%). There was no difference in either brain region or layer in the density of positively stained pyramidal cells. These data confirm mounting evidence suggesting dendritic loss in the prefrontal cortex and suggest that the loss of protein does not appear to be due to a change in the number of cells producing the protein but rather in the amount of protein being produced. Additionally, these data suggest that the loss of neurogranin may alter the calcium-calmodulin dependent pathways due to its role as a regulator of calmodulin suggesting a link between structural and functional alterations of the pyramidal cells in the prefrontal cortex.
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PMID:Evidence of altered neurogranin immunoreactivity in areas 9 and 32 of schizophrenic prefrontal cortex. 1679 25

The neurogranin (NRGN) gene produces a postsynaptic brain-specific protein that regulates calmodulin-Ca(2+) availability in neurons. Acting downstream of the NMDA receptor and upstream of calcineurin and other proteins implicated in schizophrenia, NRGN is a good candidate for association studies in schizophrenia. NRGN expression is regulated during development and is modulated by thyroid hormones and retinoids, molecules essential for the proper development of the central nervous system. Given the genetic complexity of schizophrenia and the potential genetic heterogeneity in different populations, we studied a possible association of NRGN with schizophrenia in 73 Azorean proband-parent triads and in two independent case-control samples from the Portuguese-mainland (244 schizophrenic and 210 controls) and Brazil (69 schizophrenic and 85 mentally healthy individuals). Genotype distribution showed association of the rs7113041 SNP with schizophrenia in males of Portuguese origin, which was confirmed by the analysis of the proband-parent triads. This evidence, implicating NRGN in schizophrenia, introduces another player into the glutamatergic hypothesis of schizophrenia.
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PMID:Association of the gene encoding neurogranin with schizophrenia in males. 1714 Jun 1

Schizophrenia is a severe neuropsychiatric disorder. Previous studies have implicated the prefrontal cortex (PFC) [Harrison PJ. The neuropathology of schizophrenia a critical review of the data and their interpretation. Brain 1999;122:593-624; Jones LB. Recent cytoarchitectonic changes in the prefrontal cortex of schizophrenics. Frontiers of Bioscience 2001;6:E148-53]. Recent immunocytochemical studies have shown a dramatic decrease in MAP2 and neurogranin [Jones L, Johnson N, Byne W. Alterations in MAP2 staining in area 9 and 32 of schizophrenic prefrontal cortex. Psychiatry Research 2002;114:137-48; Broadbelt K, Pamprasaud A, Jones LB. Evidence of altered neurogranin immunoreactivity in areas 9 and 32 of schizophrenic prefrontal cortex. Schizophrenia Research 2006;87:6-14] a loss of either is suggestive of dendritic lesions [Li GL, Farooque M, Lewen A., Lennmyr F, Holtz A., Olsson Y. MAP2 and neurogranin as markers for dendritic lesions in cns injury an immunohistochemical study in the rat. APMIS 2002;108:98-106.]. Neurogranin is an upstream regulator of calcium and calmodulin [Prichard L, Deloulmes JC, Storm DR. Interactions between Neurogranin and Calmodulin in vivo. Journal of Biological Chemistry 1999;274:7689-94]. A direct action of this pathway is the phosphorylation of MAP2, which is required for microtubule stabilization. Because of the above findings as well as moropholigical alterations [Broadbelt K, Byne W, Jones LB. Evidence for a decrease in primary and secondary basilar dendrites on pyramidal cells in area 32 of schizophrenic prefrontal cortex. Schizophrenia Research 2002;58:75-81] we examined the expression of the active form of calmodulin in layers III and V of areas 9 and 32 in six controls and six schizophrenics matched for age, sex, and postmortem interval. Using area fraction analysis we quantified immunostaining and counted the number of immunopositive pyramidal cells and interneurons as well as immunonegative pyramidal cells. Area fraction analysis showed a significant decrease in immunostaining in area nine layers III (58%) and V (44%), area 32 layers III (51%) and V (32%). We found a significant reduction in the density of immunopositive pyramidal cells in area 9 (11%) layer III, (20%) layer V, area 32 (16%) layer III and (17%) layer V with no difference in immunopositive interneurons. These data suggest a loss of the active form of calmodulin with pyramidal cells being preferentially affected suggesting that the calcium calmodulin dependent pathway may be altered in the pyramidal cells in the PFC.
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PMID:Evidence of altered calmodulin immunoreactivity in areas 9 and 32 of schizophrenic prefrontal cortex. 1828 58

Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.
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PMID:Common variants conferring risk of schizophrenia. 1957 8

Negative symptoms in schizophrenia respond poorly to antipsychotics, but may improve when these are augmented with selective serotonin reuptake inhibitors (SSRIs). The molecular mechanisms underlying the augmentation are unclear. Nevertheless, significant progress has been made, pointing to some candidate systems which may be involved in SSRI-antipsychotic synergism. Thus, the enhanced dopamine release by SSRI-antipsychotic treatment is modulated by specific serotonergic receptors and by tyrosine hydroxylase. There are modifications in gamma-aminobutyric acid system via glutamate decarboxylase 67, protein kinase C beta and the receptor for activated C-kinase 1 (Rack1). Some studies indicate the input of transcription and neurotrophic factors as phospho-cyclic adenosine monophosphate response element-binding protein, Fos and fibroblast growth factor-2. Alterations in calcium signaling (neurogranin, regulator of G-protein signaling and Rack1) and in cytokine receptors for interleukin-8 and chemokine have also been reported. While as yet limited in scope, the evidence suggests definable molecular targets which may be implicated in drug development based on SSRI-antipsychotic synergistic actions.
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PMID:Molecular mechanisms underlying synergistic effects of SSRI-antipsychotic augmentation in treatment of negative symptoms in schizophrenia. 1957 25

The SMARCA2 gene, which encodes BRM in the SWI/SNF chromatin-remodeling complex, was recently identified as being associated with schizophrenia (SZ) in a genome-wide approach. Polymorphisms in SMARCA2, associated with the disease, produce changes in the expression of the gene and/or in the encoded amino acid sequence. We show here that an SWI/SNF-centered network including the Smarca2 gene is modified by the down-regulation of REST/NRSF in a mouse neuronal cell line. REST/NRSF down-regulation also modifies the levels of Smarce1, Smarcd3 and SWI/SNF interactors (Hdac1, RcoR1 and Mecp2). Smarca2 down-regulation generates an abnormal dendritic spine morphology that is an intermediate phenotype of SZ. We further found that 8 (CSF2RA, HIST1H2BJ, NOTCH4, NRGN, SHOX, SMARCA2, TCF4 and ZNF804A) out of 10 genome-wide supported SZ-associated genes are part of an interacting network (including SMARCA2), 5 members of which encode transcription regulators. The expression of 3 (TCF4, SMARCA2 and CSF2RA) of the 10 genome-wide supported SZ-associated genes is modified when the REST/NRSF-SWI/SNF chromatin-remodeling complex is experimentally manipulated in mouse cell lines and in transgenic mouse models. The REST/NRSF-SWI/SNF deregulation also results in the differential expression of genes that are clustered in chromosomes suggesting the induction of genome-wide epigenetic changes. Finally, we found that SMARCA2 interactors and the genome-wide supported SZ-associated genes are considerably enriched in genes displaying positive selection in primates and in the human lineage which suggests the occurrence of novel protein interactions in primates. Altogether, these data identify the SWI/SNF chromatin-remodeling complex as a key component of the genetic architecture of SZ.
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PMID:SMARCA2 and other genome-wide supported schizophrenia-associated genes: regulation by REST/NRSF, network organization and primate-specific evolution. 2045 75

Schizophrenia is a highly heritable disorder, but the identification of specific genes has proven to be a difficult endeavor. Genes involved in the dopaminergic system are considered to be major candidates since the "dopamine hypothesis" of impairment in dopaminergic neurotransmission is one of the most widely accepted hypotheses of the etiology of schizophrenia. The overall findings from candidate studies do provide some support for the "dopamine hypothesis." However, results from the first systematic genome-wide association (GWA) studies have implicated variants within ZNF804A, NRGN, TCF4, and variants in the MHC region on chromosome 6p22.1. Although these genes may not immediately impact on dopaminergic neurotransmission, it remains possible that downstream impairments in dopaminergic function are caused. Furthermore, only a very small fraction of all truly associated genetic variants have been detected and many more associated variants will be identified in the future by GWA studies and alternative approaches. The results of these studies may allow a more comprehensive re-evaluation of the dopamine hypothesis.
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PMID:New Genetic Findings in Schizophrenia: Is there Still Room for the Dopamine Hypothesis of Schizophrenia? 2048 77

The recent advent of genome-wide mass-marker technology has resulted in renewed optimism to unravel the genetic architecture of psychotic disorders. Genome-wide association studies have identified a number of common polymorphisms robustly associated with schizophrenia, in ZNF804A, transcription factor 4, major histocompatibility complex, and neurogranin. In addition, copy number variants (CNVs) in 1q21.1, 2p16.3, 15q11.2, 15q13.3, 16p11.2, and 22q11.2 were convincingly implicated in schizophrenia risk. Furthermore, these studies have suggested considerable genetic overlap with bipolar disorder (particularly for common polymorphisms) and neurodevelopmental disorders such as autism (particularly for CNVs). The influence of these risk variants on relevant intermediate phenotypes needs further study. In addition, there is a need for etiological models of psychosis integrating genetic risk with environmental factors associated with the disorder, focusing specifically on environmental impact on gene expression (epigenetics) and convergence of genes and environment on common biological pathways bringing about larger effects than those of genes or environment in isolation (gene-environment interaction). Collaborative efforts that bring together expertise in statistics, genetics, epidemiology, experimental psychiatry, brain imaging, and clinical psychiatry will be required to succeed in this challenging task.
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PMID:REVIEW: Genome-wide findings in schizophrenia and the role of gene-environment interplay. 2055 8

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