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)

Recent imaging and postmortem studies suggest that impaired connectivity is involved in the pathophysiology of schizophrenia and major affective disorders. We investigated the presynaptic proteins complexin (Cx) I and Cx II in postmortem prefrontal cortex in schizophrenia (n = 13; six suicide, seven nonsuicide), major depression (n= 11, all suicide) and controls (n = 11) with an enzyme-linked immunoadsorbent assay (ELISA). Overall analysis indicated a significant difference between groups (F = 3.93, P = 0.007). Cx I (enriched in inhibitory terminals) was decreased 33% in schizophrenia (26% in schizophrenia/nonsuicide, 42% in schizophrenia/suicide) and 27% in major depression. Cx II (enriched in excitatory terminals) was not significantly different. Analysis of the ratio of Cx II/Cx I was carried out as an indication of the balance of excitatory to inhibitory terminals. A significant difference between groups (ANOVA, F = 6.42, P = 0.005) was observed. The mean value of Cx II/Cx I was significantly increased by 34% in schizophrenia (26% in schizophrenia/nonsuicide and 43% in schizophrenia/suicide) and by 32% in depression compared with control (Student-Newman-Keuls test, P = 0.05). Immunoreactivities of the two complexins were highly correlated in all groups. However, compared with controls and depression, samples from cases with schizophrenia appeared to have relatively less Cx I for similar amounts of Cx II. Immunocytochemical studies of rat frontal cortex after 3 weeks treatment with chlorpromazine, trifluoperazine or haloperidol revealed no differences in complexins, synaptophysin, SNAP-25, syntaxin or VAMP in comparison with animals treated with vehicle. Alterations of complexins may contribute to the molecular substrate for abnormalities of neural connectivity in severe mental disorders.
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PMID:Altered immunoreactivity of complexin protein in prefrontal cortex in severe mental illness. 1208 66

Several studies suggest that decreased expression of presynaptic proteins may be characteristic of schizophrenia. We examined one such protein, synapsin, in schizophrenia and bipolar disorder. Samples of hippocampal tissue from controls (n = 13), patients with schizophrenia (n = 16), or bipolar disorder (n = 6), and suicide victims (n = 7) were used. The membrane and cytosolic fractions were analyzed by Western immunoblotting for synapsin using an antibody that detects synapsin Ia, IIa, and IIIa proteins. Synaptophysin was also measured for comparison. Total synapsin was decreased significantly in patients with schizophrenia (P = 0.034) and in bipolar disorder (P = 0.00008) as compared to controls. The synapsin/synaptophysin ratios were decreased in schizophrenia and bipolar disorder, and additionally in suicide victims (P = 0.014). Age, postmortem interval, percentage of protein extracted, and pH of brain were not different between groups. No changes in total synapsin or synaptophysin in the hippocampus were produced by injecting rats with either lithium or haloperidol for 30 days. Reductions in synapsin in both patients with schizophrenia (synapsin IIa and IIIa) and bipolar disorder (synapsin Ia, IIa and IIIa) imply that altered or reduced synaptic function in the hippocampus may be involved in these disorders.
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PMID:Reduction of synapsin in the hippocampus of patients with bipolar disorder and schizophrenia. 1214 Jul 80

The neuropathological features of schizophrenia are suggestive of a developmentally induced impairment of synaptic connectivity. Semaphorin 3A (sema3A) might contribute to this process because it is a secreted chemorepellant which regulates axonal guidance. We have investigated sema3A in the cerebellum (an area in which expression persists in adulthood), and measured its abundance in 16 patients with schizophrenia and 16 controls. In adults, sema3A was predominantly localized to the inner part of the molecular layer neuropil, whereas infants and rats showed greater labelling of Purkinje cell bodies. Sema3A was increased in schizophrenia, as shown by enzyme-linked immunosorbent assay (+28%; P<0.05) and immunohistochemistry (+45%; P<0.01). We also measured reelin mRNA, since reelin is involved in related developmental processes and is decreased in other brain regions in schizophrenia. Reelin mRNA showed a trend reduction in the subjects with schizophrenia (-26%; P=0.07) and, notably, was negatively correlated with sema3A. Sema3A also correlated negatively with synaptophysin and complexin II mRNAs. The results show that sema3A is elevated in schizophrenia, and is associated with downregulation of genes involved in synaptic formation and maintenance. In this respect, sema3A appears to contribute to the synaptic pathology of schizophrenia, perhaps via ongoing effects of persistent sema3A elevation on synaptic plasticity. The findings are consistent with an early neurodevelopmental origin for the disorder, and the reciprocal changes in sema3A and reelin may be indicative of a pathogenic mechanism that affects the balance between trophic and inhibitory factors regulating synaptogenesis.
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PMID:The axonal chemorepellant semaphorin 3A is increased in the cerebellum in schizophrenia and may contribute to its synaptic pathology. 1261 Jun 47

Dysfunction of the prefrontal cortex in schizophrenia may be associated with abnormalities in synaptic structure and/or function and reflected in altered concentrations of proteins in presynaptic terminals and involved in synaptic plasticity (synaptobrevin/ vesicle-associated membrane protein (VAMP), synaptosomal-associated protein-25 (SNAP-25), syntaxin, synaptophysin and growth-associated protein-43 (GAP-43)). We examined the immunoreactivity of these synapse-associated proteins via quantitative immunoblotting in the prefrontal cortex of patients with schizophrenia (n=18) and in normal controls (n=23). We also tested the stability of these proteins across successive post-mortem intervals in rat brains (at 0, 3, 12, 24, 48, and 70 h). To investigate whether experimental manipulation of prefrontal cortical development in the rat alters prefrontal synaptic protein levels, we lesioned the ventral hippocampus of rats on postnatal day 7 and measured immunoreactivity of presynaptic proteins in the prefrontal cortex on postnatal day 70. VAMP immunoreactivity was lower in the schizophrenic patients by 22% (P<0.03). There were no differences in the immunoreactivity of any other proteins measured in schizophrenic patients as compared to the matched controls. Proteins were fairly stable up to 24 h and thereafter the abundance of most proteins examined was significantly reduced (falling to as low as 20% of baseline levels at 48-70 h). VAMP immunoreactivity was higher in the lesioned rats as compared to sham controls by 22% (P&<0.03). There were no significant differences between the lesioned rats and sham animals in any other presynaptic protein. These data suggest that apparently profound prefrontal cortical dysfunction in schizophrenia, as well as in an animal model of schizophrenia, may exist without gross changes in the abundance of many synaptic proteins but discrete changes in selected presynaptic molecules may be present.
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PMID:Presynaptic proteins in the prefrontal cortex of patients with schizophrenia and rats with abnormal prefrontal development. 1293 Dec 7

Post-weaning social isolation-rearing of rats leads to behavioural and neurochemical sequelae that model aspects of schizophrenia, and it may be useful to test hypotheses related to putative molecular mechanisms of the illness. In humans, the presynaptic protein CDCrel-1 represents an interesting candidate molecule for the mechanism and aetiology of schizophrenia. CDCrel-1 modulates dopamine neurotransmission, binds to the SNARE protein syntaxin and maps onto a region of chromosome 22q11 deleted in velo-cardio-facial and DiGeorge syndromes, which are associated with increased prevalence of schizophrenia. Using the isolation-rearing model, we measured immunoreactivity of the synaptic proteins CDCrel-1, synaptophysin and syntaxin. Male, Sprague-Dawley rats were raised in groups or in isolation for 12 weeks from weaning. Synaptic protein immunoreactivities were measured in striatal and hippocampal homogenates, using a sensitive enzyme-linked immunoadsorbent assay with monoclonal antibodies. Isolation-rearing produced region- and protein-specific effects. CDCrel-1 immunoreactivity was significantly lower in the striatum and marginally higher in the hippocampus of isolation-reared compared with socially reared animals. There were no statistically significant differences in synaptophysin immunoreactivity in either region. Confocal microscopy demonstrated a high degree of colocalization between the two presynaptic proteins. In striatum, a robust relationship between CDCrel-1 and syntaxin immunoreactivities was observed in socially reared rats, this was lost in the isolation-reared animals. Altered levels of the septin CDCrel-1 in isolation-reared rats may contribute to changes in neuronal connectivity and neurotransmission, and suggest a potential role for CDCrel-1 in schizophrenia related to chromosome 22q11 deletion syndrome.
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PMID:Abnormalities of presynaptic protein CDCrel-1 in striatum of rats reared in social isolation: relevance to neural connectivity in schizophrenia. 1524 2

Growth-associated protein 43 (GAP-43) expression is critical for the proper establishment of neural circuitry, a process thought to be disrupted in schizophrenia. Previous work from our laboratory demonstrated decreased GAP-43 levels in post-mortem tissue from the entire hippocampal formation of affected individuals. In the present study, we used immunocytochemical techniques to localize alterations in GAP-43 protein to specific synapses. GAP-43 distribution was compared to that of synaptophysin, another synaptic protein known to be altered in schizophrenia. The levels and distribution of GAP-43 and synaptophysin proteins were measured in the dentate gyrus of subjects with schizophrenia and sex-, age-, and postmortem interval-matched normal controls and subjects with bipolar disorder. Tissue from subjects was provided by the Harvard Brain Tissue Resource Center. In control subjects, GAP-43 immunostaining was prominent in synaptic terminals in the inner molecular layer and hilar region. Subjects with schizophrenia had significant decreases in GAP-43 immunoreactivity in the hilus (p<0.05, paired t-test) and inner molecular layer (p<0.05, paired t-test) but not in the outer molecular layer. In the same tissues, synaptophysin immunoreactivity was significantly reduced in both the inner and outer molecular layers of the dentate gyrus (both p<0.01 by paired t-test), but not in the hilus. In contrast to patients with schizophrenia, GAP-43 and synaptophysin levels in subjects with bipolar disorder did not differ from controls. Given the relationship of GAP-43 and synaptophysin with the development and plasticity of synaptic connections, the observed alterations in the hippocampus of patients with schizophrenia may be related to cognitive deficits associated with this illness.
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PMID:Growth-associated protein 43 (GAP-43) and synaptophysin alterations in the dentate gyrus of patients with schizophrenia. 1569 36

The extracellular region of the transmembrane neural cell adhesion molecule (NCAM-EC) is shed as a soluble fragment at elevated levels in the schizophrenic brain. A novel transgenic mouse line was generated to identify consequences on cortical development and function of expressing soluble NCAM-EC from the neuron-specific enolase promoter in the developing and mature neocortex and hippocampus. NCAM-EC transgenic mice exhibited a striking reduction in synaptic puncta of GABAergic interneurons in the cingulate, frontal association cortex, and amygdala but not hippocampus, as shown by decreased immunolabeling of glutamic acid decarboxylase-65 (GAD65), GAD67, and GABA transporter 1. Interneuron cell density was unaltered in the transgenic mice. Affected subpopulations of interneurons included basket interneurons evident in NCAM-EC transgenic mice intercrossed with a reporter line expressing green fluorescent protein and by parvalbumin staining. In addition, there appeared to be a reduction in excitatory synapses, as revealed by synaptophysin staining and apical dendritic spine density of cortical pyramidal cells. Behavioral analyses demonstrated higher basal locomotor activity of NCAM-EC mice and enhanced responses to amphetamine and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate compared with wild-type controls. Transgenic mice were deficient in prepulse inhibition, which was restored by clozapine but not by haloperidol. Additionally, NCAM-EC mice were impaired in contextual and cued fear conditioning. These results suggested that elevated shedding of NCAM perturbs synaptic connectivity of GABAergic interneurons and produces abnormal behaviors that may be relevant to schizophrenia and other neuropsychiatric disorders.
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PMID:Neural cell adhesion molecule-secreting transgenic mice display abnormalities in GABAergic interneurons and alterations in behavior. 1587 14

Olfactory deficits, observed in schizophrenia, may be associated with a disruption of synaptic transmission in the olfactory system. Using immunohistochemistry and optical densitometry, we assessed the integrity of the synaptic connection between olfactory receptor neurons and olfactory bulb target neurons in schizophrenia by comparing the level of eight proteins, expressed in the olfactory bulb glomeruli, among schizophrenia and control subjects. In schizophrenia, no change was observed in the levels of OMP, GAP43 and NCAM, proteins expressed by olfactory receptor neurons, suggesting an intact innervation of the olfactory bulb by these neurons. This was supported by the absence of change in calbindin level, which has been shown to decrease after the destruction of the olfactory epithelium. The level of synaptophysin, a pre-synaptic protein, was also unchanged. These findings suggested that axons of olfactory receptor neurons establish synapses with their olfactory bulb targets in schizophrenia. The absence of change in the level of poorly phosphorylated neurofilament of moderate and high molecular weight (NFM/HP) suggested no lack of dendritic innervation despite a previously seen reduction of glomerular MAP2 level in schizophrenia subjects. This and above findings were consistent with the absence of change in the level of beta-tubulin III, a protein expressed by neurons of both olfactory epithelium and bulb. Finally, we noted no significant decrease in trkB level, a neurotrophin receptor involved in the olfactory epithelium maintenance. This study showed no evidence of major structural alteration of the synapse between the olfactory epithelium and bulb in schizophrenia.
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PMID:Characterization of olfactory bulb glomeruli in schizophrenia. 1594 25

Recent studies indicate that levels of presynaptic proteins are altered in the post-mortem brain in schizophrenia. In particular, the hippocampus exhibits reduced levels of synaptophysin and the SNARE protein SNAP-25. The effects of treatment with antipsychotic drugs on levels of SNAP-25 in the hippocampus remains unknown. To determine the effects of typical antipsychotic drugs on levels of synaptophysin and SNAP-25 in the hippocampus, rats were treated with chlorpromazine, haloperidol or trifluoperazine for 21 d. Quantitative immunohistochemistry was used to measure immunoreactivity within the trisynaptic circuit of the hippocampus. Trifluoperazine decreased synaptophysin within the Schaffer collateral region of the radiatum lacunosum in CA1, while haloperidol and chlorpromazine increased SNAP-25 throughout the trisynaptic pathway of the hippocampus, with strongest effects in the mossy fibre region of CA3. These results indicate that presynaptic proteins represent a potential molecular substrate for the effects of antipsychotic drugs on hippocampal synaptic connectivity.
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PMID:Selective effects of typical antipsychotic drugs on SNAP-25 and synaptophysin in the hippocampal trisynaptic pathway. 1631 83

Calcineurin (protein phosphatase 2B) is a calcium-dependent serine-threonine phosphatase. It has diverse roles and is centrally involved in synaptic plasticity. The catalytic A subunit of calcineurin has three isoforms, alpha, beta and gamma. Their expression and ontogeny in the brain has not been systematically investigated; such data become important with a report that PPP3CC, the gene encoding calcineurin Agamma, is a susceptibility gene for schizophrenia, and the finding that its expression is decreased in the disorder. We used in situ hybridization histochemistry to measure the relative transcript abundance of calcineurin Agamma and the other catalytic isoforms, Aalpha and Abeta, during development of the Sprague-Dawley rat hippocampus and cerebellum. All three isoforms are present in both regions at all time points [embryonic day 19 (E19) to postnatal day 42 (P42)] and undergo developmental regulation, but differ in their ontogenic profile. Calcineurin Aalpha and Abeta mRNAs increased from E19 through to adulthood, whereas Agamma mRNA was most highly expressed during early developmental stages. Calcineurin Aalpha and Abeta mRNAs positively correlated with synaptophysin mRNA (a synaptic marker), whilst Agamma mRNA was either unrelated to, or negatively correlated, with this transcript. These data confirm that all three calcineurin A subunits are expressed in the rodent brain, and indicate that calcineurin Agamma may have different roles than Aalpha and Abeta. The data also suggest a potential importance of calcineurin Agamma in neurodevelopment, and in the genetically influenced neurodevelopmental disturbance that is thought to underlie schizophrenia.
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PMID:Differential expression of calcineurin A subunit mRNA isoforms during rat hippocampal and cerebellar development. 1636 68

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