Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The alterations in brain function and structure seen in schizophrenia are mediated by genetics as well as vulnerability due to environmental factors. Postmortem studies in schizophrenic patients have shown that expression of complexin II, which is involved in neurotransmitter release at central nervous system synapses, is decreased in the brain. We examined the physiological characteristics of complexin II gene-deficient mice subjected to maternal deprivation stress to determine whether psychological stress during the early stage of life affected the development of brain function. We compared the electrophysiological properties of CA1 hippocampal pyramidal neurons and spatial memory in the Morris water maze test in the wild-type mouse and the homozygous mutant. In the non-stressed mouse, no significant differences in transsynaptic responses and synaptic plasticity or spatial memory were seen, suggesting that complexin II does not play a critical role in transmitter release or synaptic plasticity under these conditions. In contrast, under conditions of maternal deprivation stress, the knockout mouse showed a significant decrease in post-tetanic potentiation and LTP induction and a significant impairment in Morris water Maze test compared to the wild-type mouse, suggesting that complexin II plays a significant role in neurotransmitter release and synaptic plasticity under this pathological condition. Taken together, these results show that mice lacking complexin II are vulnerable to maternal deprivation stress, which raises the possibility that the complexin II gene may be a factor in the onset of schizophrenia.
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PMID:Vulnerability of synaptic plasticity in the complexin II knockout mouse to maternal deprivation stress. 1611 91

The subiculum plays a key role in processing neuronal information from the hippocampus to different cortical and subcortical brain regions. The subicular projections to the nucleus accumbens and the prefrontal cortex have received increasing attention, as alterations of their activity seem to be involved in schizophrenia. Phencyclidine and other non-competitive antagonists of NMDA receptors (such as ketamine and MK-801) induce psychotic effects in humans that closely resemble the positive, negative and cognitive symptoms of schizophrenia. Using the MK-801 model of psychosis, we investigated the time course of alterations of synaptic transmission and plasticity at CA1-subiculum synapses of hippocampal brain slices 4 h, 24 h and 4 weeks after MK-801 treatment. We report here that systemic application of MK-801 causes a facilitation of LTP at CA1-subiculum synapses 24 h after treatment as compared with control LTP. Four weeks after MK-801 treatment, the magnitude of LTP reversed to control values. The priming of LTP 24 h after systemic application of MK-801 suggest a new form of metaplasticity that sheds light on the delayed facilitating effect of this drug on synaptic efficacy.
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PMID:Enhancement of long-term potentiation at CA1-subiculum synapses in MK-801-treated rats. 1618 95

Implicated as a key structure in the pathophysiology of schizophrenia, the hippocampus is at the forefront of neuropathological and neuroimaging research. To elucidate the cellular basis of hippocampal pathology in schizophrenia, we studied the postmortem hippocampal sections of 16 patients suffering from schizophrenia and 16 controls applying the gray-level index (GLI) method. We determined the area-percentage covered by neuronal perikarya in relation to the total area of the pyramidal cell layer in the four subdivisions of the ammon's horn (cornu ammonis, CA1-4) bilaterally. Additionally, we determined the area size of the pyramidal cell layer (CA1-4) and dentate gyrus (DG) granule cell layer. Results showed no significant differences between diagnostic groups with respect to the dependent variables, supporting the view that there is no primary alteration of hippocampal gray matter in schizophrenia.
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PMID:Intact hippocampal gray matter in schizophrenia as revealed by automatized image analysis postmortem. 1618 39

A decrease in alpha7 nicotinic acetylcholine receptors in the hippocampus has been hypothesized to contribute to alterations in auditory gating and other behavioral impairments in schizophrenia. However, while both typical and atypical neuroleptics are routinely used in the therapeutics of schizophrenia, little is known about their effects on auditory gating or alpha7 nicotinic acetylcholine receptor expression particularly when they are administered for extended periods of time (which is common in the clinical setting). In the present study in normal rats, the residual effects of prior chronic treatment (90 or 180 days) with representative typical and atypical neuroleptics (oral haloperidol, 2.0 mg/kg/day; chlorpromazine, 10.0 mg/kg/day, risperidone, 2.5 mg/kg/day; or olanzapine, 10.0 mg/kg/day) on prepulse inhibition of the auditory gating response were investigated. The densities of alpha7 nicotinic acetylcholine receptors were subsequently measured using [125I]-alpha-bungarotoxin autoradiography. The results indicated that none of the compounds significantly altered the startle amplitude or prepulse inhibition response either during drug treatment (day 60) or after 90 or 180 days of treatment (i.e. during a drug free washout). However, prior exposure to chlorpromazine, risperidone and olanzapine for 90 days resulted in modest but significant (P<0.01) decreases in [125I]-alpha-bungarotoxin binding sites in some brain regions (e.g. posterior cortical amygdala). After 180 days of treatment, decreases in [(125I]-alpha-bungarotoxin binding ranging from approximately 12% (lateral dentate gyrus) up to 24% (e.g. CA1 hippocampal region) were evident in the risperidone group in 13 of the 36 regions analyzed while decreases associated with the other neuroleptics agents were still present, but not statistically significant. These data indicate that the commonly used atypical neuroleptic, risperidone is associated with time dependent and persistent negative effects on an important biological substrate of memory (i.e. the alpha7 nicotinic receptor), but that the magnitude of the deficits was not sufficient to impair auditory gating.
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PMID:Chronic exposure to typical or atypical antipsychotics in rodents: temporal effects on central alpha7 nicotinic acetylcholine receptors. 1621 23

Neuregulin-1 (NRG-1) has been identified genetically as a schizophrenia susceptibility gene, but its function in the adult brain is unknown. Here, we show that NRG-1beta does not affect basal synaptic transmission but reverses long-term potentiation (LTP) at hippocampal Schaffer collateral-->CA1 synapses in an activity- and time-dependent manner. Depotentiation by NRG-1beta is blocked by two structurally distinct and selective ErbB receptor tyrosine kinase inhibitors. Moreover, ErbB receptor inhibition increases LTP at potentiated synapses and blocks LTP reversal by theta-pulse stimuli. NRG-1beta selectively reduces AMPA, not NMDA, receptor EPSCs and has no effect on paired-pulse facilitation ratios. Live imaging of hippocampal neurons transfected with receptors fused to superecliptic green fluorescent protein, as well as quantitative analysis of native receptors, show that NRG-1beta stimulates the internalization of surface glutamate receptor 1-containing AMPA receptors. This novel regulation of LTP by NRG-1 has important implications for the modulation of synaptic homeostasis and schizophrenia.
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PMID:Neuregulin-1 reverses long-term potentiation at CA1 hippocampal synapses. 1622 46

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

Increasing evidence suggests that the metabolism of glutathione, an endogenous redox regulator, is abnormal in schizophrenia. Patients show a deficit in glutathione levels in the cerebrospinal fluid and prefrontal cortex and a reduction in gene expression of the glutathione synthesizing enzymes. We investigated whether such glutathione deficit altered synaptic transmission and plasticity in slices of rat hippocampus, with particular emphasis on NMDA receptor function. An approximately 40% decrease in brain glutathione levels was induced by s.c. administration of L-buthionine-(S,R)-sulfoximine, an inhibitor of glutathione synthesis. Such glutathione deficit did not affect the basal synaptic transmission, but produced several NMDA receptor-dependent and -independent effects. Glutathione deficit caused an increase in excitability of CA1 pyramidal cells. The paired-pulse facilitation was diminished in glutathione-depleted slices, in a manner that was independent of NMDA receptor activity. This suggests that lowering glutathione levels altered presynaptic mechanisms involved in neurotransmitter release. NMDA receptor-dependent long-term potentiation induced by high-frequency stimulation was impaired in glutathione-depleted slices. Pharmacologically isolated NMDA receptor-mediated field excitatory postsynaptic potentials were significantly smaller in L-buthionine-(S,R)-sulfoximine-treated than in control slices. Hypofunction of NMDA receptors under glutathione deficit was explained at least in part by an excessive oxidation of the extracellular redox-sensitive sites of the NMDA receptors. These results indicate that a glutathione deficit, like that observed in schizophrenics, alters short- and long-term synaptic plasticity and affects NMDA receptor function. Thus, glutathione deficit could be one causal factor for the hypofunction of NMDA receptors in schizophrenia.
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PMID:Synaptic plasticity impairment and hypofunction of NMDA receptors induced by glutathione deficit: relevance to schizophrenia. 1633 Jan 53

The heterozygote reeler mouse (HRM) shows many neuroanatomical and biochemical features that are also present in some human cognitive disorders, such as schizophrenia. In the present study, hippocampal dependent plasticity and cognitive function of the HRM were characterized in detail in an attempt to reveal phenotypic functional differences that result from Reelin haploinsufficiency. The HRM and wild type mice show similar levels of overall activity, coordination, thermal nociception, startle responses, and anxiety-like behavior. In addition, both genotypes show similar shock threshold, identical cued freezing behavior and comparable spatial learning in Morris water maze tasks. However, a significant reduction in contextual fear conditioned learning was observed in the HRM. Electrophysiological studies in hippocampal CA1 synapses revealed a plethora of differences between genotypes. The HRM exhibits reduced field excitatory postsynaptic potentials in responses to similar synaptic inputs, lowered paired pulse facilitation ratio and impaired long-term depression and tetanus-induced long-term potentiation (LTP). Also, deficits were detected in LTP elicited by theta burst stimulation or by a whole cell pairing protocol. These physiologic differences could not be accounted for by changes in the overall amount of glutamate receptor subunits. In addition, it was determined that network-driven excitatory and inhibitory activities recorded in CA1 pyramidal neurons showed that the HRM had comparable amplitude and frequency of spontaneous excitatory postsynaptic currents, but a marked reduction in spontaneous inhibitory postsynaptic currents. Thus, the HRM exhibits a specific hippocampal-dependent learning deficit accompanied with a pronounced impairment of hippocampal plasticity and functional inhibitory innervation.
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PMID:Cognitive disruption and altered hippocampus synaptic function in Reelin haploinsufficient mice. 1637 15

The paper promotes the view that the alert brain alternates between operating in an action mode, based on frontal lobe function, and a receptive mode, involving cholinergic system activity. Their alternation forms a conversation with the environment. It is hypothesized that competition between the modes centers on control over excitability of neurons in the CA1 field of the hippocampus. Increased excitability enhances the flow of hippocampal output through the subiculum resulting in support for frontal lobe function and the action mode. Decreased excitability, on the other hand, reduces this output and that support, leading to a disconnection between frontal lobes and hippocampus. At the same time, correlated cholinergic activity enhances receptive mode processes, indicated by the occurrence of the hippocampal theta rhythm. It is suggested that the hypothesis provides a conceptual framework for considering various phenomena including REM sleep, schizophrenia, and hypnosis. In REM sleep the receptive mode remains dominant as cholinergic activity supports the hippocampal integration of experience into a composite view of reality. In schizophrenia, the action and receptive modes are not properly coordinated because of a dysfunction in anterior hippocampal output. And hypnosis might be seen as a process in which conditions and suggestions are able to induce in some people a prolonged occurrence of the receptive mode allowing a normal view of reality to be altered.
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PMID:The conversational brain: fronto-hippocampal interaction and disconnection. 1682 1

Variations in the gene encoding the novel protein dysbindin-1 (DTNBP1) are among the most commonly reported genetic variations associated with schizophrenia. Recent studies show that those variations are also associated with cognitive functioning in carriers with and without psychiatric diagnoses, suggesting a general role for dysbindin-1 in cognition. Such a role could stem from the protein's known ability to affect neuronal glutamate release. How dysbindin-1 might affect glutamate release nevertheless remains unknown without the discovery of the protein's neuronal binding partners and its subcellular locus of action. We demonstrate here that snapin is a binding partner of dysbindin-1 in vitro and in the brain. Tissue fractionation of whole mouse brains and human hippocampal formations revealed that both dysbindin-1 and snapin are concentrated in tissue enriched in synaptic vesicle membranes and less commonly in postsynaptic densities. It is not detected in presynaptic tissue fractions lacking synaptic vesicles. Consistent with that finding, immunoelectron microscopy showed that dysbindin-1 is located in (i) synaptic vesicles of axospinous terminals in the dentate gyrus inner molecular layer and CA1 stratum radiatum and in (ii) postsynaptic densities and microtubules of dentate hilus neurons and CA1 pyramidal cells. The labeled synapses are often asymmetric with thick postsynaptic densities suggestive of glutamatergic synapses, which are likely to be derived from dentate mossy cells and CA3 pyramidal cells. The function of dysbindin-1 in presynaptic, postsynaptic and microtubule locations may all be related to known functions of snapin.
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PMID:Dysbindin-1 is a synaptic and microtubular protein that binds brain snapin. 1698 Mar 28


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