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 clinical histories of 102 schizophrenics who died at 70 years of age or older were reviewed. The incidence of neurofibrillary tangles (NFTs) was two times higher in the patients who received (74%) than in those who did not receive (36%) treatment with neuroleptics. The development of NFTs started earlier in the treated group. Further studies comparing brains of nine schizophrenics (average age, 86 years) who did not receive treatment with neuroleptics and seven age-matched cases who received neuroleptics, both with neurofibrillary pathology and neuritic plaques, showed characteristic differences. The numerical density of NFTs was slightly greater in the cornu Ammonis (CA1 and CA2) and subiculum of treated patients. Significantly lower numerical density and lower percentage of pretangles (stage 0) and early and mature tangles (stages 1 and 2) and increased number of end-stage tangles (stage 3) were found in the CA, subicular complex, and cerebral cortex of the treated group. These changes suggest accelerated neurofibrillary degeneration in neurons. A significant increase in the numerical density of tau-1-positive plaques was observed in sector CA1 of the CA (from 0.15/mm2 to 17.36/mm2), subiculum (from 0/mm2 to 16.62/mm2), temporal cortex (from 0.14/mm2 to 9.46/mm2), and occipital cortex (from 0.08/mm2 to 0.39/mm2). The higher numerical density of tau-1-positive plaques, but not of 4G8-positive plaques, indicates acceleration of neurofibrillary changes in the plaques of patients treated with neuroleptics. The significant decrease (20-25%) in the numerical density of neurons in the pyramidal layer of sectors 2-4 in the CA appears to be associated with accelerated neurofibrillary changes in neurons and plaques in the treated group. This study demonstrates that chronic treatment with neuroleptics--not schizophrenia itself--significantly increases the risk of more frequent, earlier, and accelerated development of neurofibrillary pathology in the brains of elderly schizophrenics.
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PMID:Neurofibrillary pathology in brains of elderly schizophrenics treated with neuroleptics. 788 52

Neuropsychological testing of elderly schizophrenic patients reveals that a significant portion of this population exhibit varying degrees of cognitive impairment. Since Alzheimer's disease is the most common cause of dementia in geriatric patients, we investigated whether the cognitive decline observed in schizophrenia is the result of degenerative changes analogous to those characteristic of Alzheimer's disease. For this purpose, the number and distribution of senile plaques and neurofibrillary tangles were mapped in the hippocampi of 10 cognitively impaired schizophrenic patients, 10 patients with Alzheimer's disease, and 10 patients with dementia not attributed to either schizophrenia or Alzheimer's disease. In Alzheimer's disease, degenerative changes invariably predominated in the CA1 subfield, subiculum, and proisocortex. By contrast, findings characteristic of Alzheimer's disease were virtually never observed in the hippocampi of schizophrenic and other cognitively impaired patients. In some patients with Alzheimer's disease, the presence of senile plaques in the molecular layer of the dentate gyrus suggested the existence of an underlying entorhinal cortex lesion. Similar dentate gyrus pathology was never found in any of the other patients. The authors conclude that cognitive impairment in schizophrenia is not the result of degenerative changes analogous to those found in Alzheimer's disease.
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PMID:A topographical study of senile plaques and neurofibrillary tangles in the hippocampi of patients with Alzheimer's disease and cognitively impaired patients with schizophrenia. 814 Jan 81

Whole-cell and extracellular recording techniques were used to examine local circuit inhibition in the CA1 region of the rat hippocampus in vitro. Activation, primarily of the recurrent inhibitory circuit by alvear stimulation, elicited an IPSP in pyramidal neurons that was dependent, in part, on NMDA receptor activation. Application of a tetanizing stimulus to the alveus evoked long-term potentiation (LTP) of the intracellularly recorded recurrent IPSPs. This LTP also was NMDA-dependent and was more sensitive to blockade by the NMDA antagonists 2-amino-5-phosphonovalerate (APV) and N-acetyl-aspartyl-glutamate, than the excitatory LTP produced by Schaffer collateral stimulation. With regard to APV, the sensitivity of inhibitory LTP was an order of magnitude greater. A biophysical simulation of hippocampal CA1 circuitry was used in a model of learned pattern recognition that included LTP in both excitatory and inhibitory recurrent circuits. In this model, selective blockade of inhibitory LTP produced aberrant spread of lateral excitation, resulting in confusion of normally distinguishable patterns of neuronal activity. Consideration is given to the possibility that selective disruption of NMDA-dependent modulation of local circuit inhibition may serve as a model for some aspects of dysfunction associated with NMDA-antagonist exposure and schizophrenia.
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PMID:NMDA-dependent modulation of CA1 local circuit inhibition. 860 48

Phencyclidine and related compounds such as MK-801 produce psychotic symptoms, which closely resemble schizophrenia. MK-801 causes lesions in different corticolimbic regions including the medial entorhinal cortex (mEC). Using electrophysiological recordings in brain slices we tested whether several hours of systemic administration of MK-801 affect stimulus-induced field potentials (FPs) in the mEC. Stimulus-induced FPs were selectively reduced in layer III, but not in layers II and V of the mEC. In contrast, MK-801 applied acutely over the bath in low concentration had no significant effect on evoked FPs. Since the principal cells of layer III project directly to area CA1 and the subiculum, the selective effects of MK-801 may have implications for the transfer of information to the hippocampus.
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PMID:Systemic administration of the phencyclidine compound MK-801 affects stimulus-induced field potentials selectively in layer III of rat medial entorhinal cortex. 912 8

Brains from patients with therapy-refractory schizophrenia were examined with respect to pyramidal cell disarray in the hippocampus, a finding reported in some studies, but not confirmed in others. A significantly higher number of disarrayed cells was seen in the brains of the schizophrenic patients in all subfields of the Cornu Ammonis (CA) investigated. Compared with controls the schizophrenic patients also had significantly fewer pyramidal cells in the observed areas of CA1-CA3, but not in CA4. There were no signs of gliosis. Finally, there was a significant negative correlation between the number of disarrayed cells and the total number of pyramidal cells in CA1-3 in the group of probands and controls taken together, a finding interpreted as lending support to the idea of a prenatal migratory disturbance in the pathogenesis of schizophrenic syndromes.
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PMID:Hippocampal pyramidal cell disarray correlates negatively to cell number: implications for the pathogenesis of schizophrenia. 922 4

Microtubule-associated proteins (MAPs) are central to the development of normal neuronal cytoarchitecture and have been suggested in previous studies to be altered in schizophrenia. We investigated hippocampal phosphorylated and non-phosphorylated MAP2 expression in schizophrenia in relation to neuronal orientation and interneuronal distance. One paraffin embedded mid-hippocampal block was obtained from each of 8 schizophrenic and 11 control postmortem brains and immunohistochemistry for the phosphorylated and non-phosphorylated forms of MAP2 performed. Within the corona ammonis (CA) subregions and the subiculum, we assessed densitometry readings for non-phosphorylated MAP2-positive neurones (MAP2-NP), and counted the number of neurones immunopositive for phosphorylated MAP2 (MAP2-P). Using image analysis computer software we measured interneuronal distances and neuronal orientation. While there were no overall alterations in densitometric density of MAP2-NP neurones in any hippocampal subregions, we found a left-sided increase in densitometric density of MAP2-NP neurones within the subiculum (F = 8.740, P < 0.021), and the CA1 (F = 7.044, P < 0.033) of schizophrenic subjects which were unrelated to age, postmortem interval or neuroleptic exposure. There was no accompanying alteration of interneuronal distances, neuronal orientation. The findings support previous work demonstrating altered subicular MAP2 expression in schizophrenia and indicate that the finding may be lateralised. However, in contrast to previous investigations, we have demonstrated this alteration in MAP2 expression is due to an increase in the non-phosphorylated form of MAP2, rather than a decrease in total MAP2 expression. These findings suggest that cytoskeletal assembly is abnormal in schizophrenia and generate testable hypotheses regarding the developmental basis of the disorder.
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PMID:Alterations in hippocampal non-phosphorylated MAP2 protein expression in schizophrenia. 931 96

The alpha 7-nicotinic receptor (nAChR)-selective agonist choline and nAChR-subtype-selective antagonists led to the discovery that activation of both alpha 7 and alpha 4 beta 2 nAChRs located in CA1 interneurons in slices taken from the rat hippocampus facilitates the tetrodotoxin (TTX)-sensitive release of gamma-aminobutyric acid (GABA). Experiments carried out in cultured hippocampal neurons not only confirmed that preterminal alpha 7 and alpha 4 beta 2 nAChRs modulate the TTX-sensitive release of GABA, but also demonstrated that evoked release of GABA is reduced by rapid exposure of the neurons to acetylcholine (ACh, 10 microM-1 mM) in the presence of the muscarinic receptor antagonist atropine (1 microM). This effect of ACh, which is fully reversible and concentration-dependent, is partially blocked by superfusion of the cultured neurons with external solution containing either the alpha 7-nAChR-selective antagonist methyllycaconitine (MLA, 1 nM) or the alpha 4 beta 2-nAChR-selective antagonist dihydro-beta-erythroidine (DH beta E, 100 nM). A complete blockade of ACh-induced reduction of evoked release of GABA was achieved only when the neurons were perfused with external solution containing both MLA and DH beta E, suggesting that activation of both alpha 7 and alpha 4 beta 2 nAChRs modulates the evoked release of GABA from hippocampal neurons. Such mechanisms may account for the apparent involvement of nAChRs in the psychological effects of tobacco smoking, in brain disorders (e.g., schizophrenia and epilepsy), and in physiological processes, including cognition and nociception.
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PMID:Contribution of nicotinic receptors to the function of synapses in the central nervous system: the action of choline as a selective agonist of alpha 7 receptors. 978 29

The perforant path input (pp) is a major direct source of specific sensory information for the CA1 hippocampal region. The termination area of this pathway, the stratum lacunosum-moleculare, has the highest concentration of dopamine receptors in the hippocampus. We have examined the properties of the pp input and its modulation by dopamine. The input is glutamatergic and has a larger NMDA component than the Schaffer collateral (sc) input. Dopamine strongly inhibits the response to pp stimulation (IC50 approximately 3 microM) but not the response to sc stimulation. Dopamine reduces both the NMDA and AMPA components of transmission at the pp and increases paired-pulse facilitation. In the sc, the NMDA component but not the AMPA component is decreased, and paired-pulse facilitation is not affected. The effect of dopamine on the pp does not depend on GABAA inhibition but is reduced by the antagonists of both D1 and D2 families of dopamine receptors. The effect is not completely blocked by the combination of D1 and D2 antagonists, but is completely blocked by the atypical neuroleptic clozapine. Our results provide the first evidence for strong dopaminergic control of transmission in the perforant path. By inhibiting this pathway, dopamine hyperfunction and/or NMDA hypofunction abnormalities implicated in schizophrenia may isolate CA1 from its main source of sensory information.
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PMID:Dopamine selectively inhibits the direct cortical pathway to the CA1 hippocampal region. 995 20

Isolation rearing of rat pups from weaning produces neurochemical and behavioural changes that may have relevance to the neurodevelopmental basis of neuropsychiatric disorders such as schizophrenia. Although limited, studies have begun to probe for neuroanatomical changes produced by isolation rearing. In the present study, rat pups were reared in isolation, i.e., housed one per cage, from weaning. After 8 weeks of isolation, 'isolates' were compared to their socially reared controls (housed three per cage) in two behavioural paradigms: locomotor activity in a novel open field and prepulse inhibition (PPI) of the acoustic startle response. Subsequently, all rats were sacrificed and their brains removed. The hippocampus was sectioned and analysed immunohistochemically using an antibody to the synapse-specific protein synaptophysin, to gain an estimate of the synaptic content of selected hippocampal subfields. Isolates demonstrated locomotor hyperactivity and deficits in PPI relative to socially reared controls. Analysis of synaptophysin immunoreactivity suggested that isolates had significantly reduced synaptic content in the hippocampal dentate gyrus molecular layer, with smaller, non-significant reductions in the CA1 and CA3 regions. This pattern of change may be consistent with reduced neuronal input to the dentate gyrus via the entorhinal cortex, suggesting developmental changes in hippocampal-cortical circuitry. These preliminary studies extend the characterisation of isolation rearing as a model for the investigation of neurodevelopmental diseases such as schizophrenia.
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PMID:Reduced synaptophysin immunoreactivity in the dentate gyrus of prepulse inhibition-impaired isolation-reared rats. 1019 49

Most in situ hybridization histochemistry studies of messenger RNA in human brain have been carried out on frozen tissue. Recently, autoclaving has been reported to enable routinely processsed material to be used for in situ localization of messenger RNA. We have investigated whether autoclaving also permits in situ hybridization histochemistry to be used quantitatively. To do this, we targeted synaptophysin messenger RNA with a 35S-labelled oligonucleotide probe in autoclaved, formalin-fixed, paraffin wax-embedded sections of the hippocampal formation of 11 schizophrenics and 11 controls. We compared the results with those seen on frozen sections from adjacent blocks, which had been used previously to demonstrate a loss of the messenger RNA in schizophrenia. Synaptophysin messenger RNA was readily detected in the autoclaved sections. The hybridization signal correlated strongly with that seen in the frozen sections. We found a similar pattern and magnitude of decreased synaptophysin messenger RNA in schizophrenia in the autoclaved sections as we had in the frozen sections, including the selective preservation of synaptophysin messenger RNA in CA1. The reduction of synaptophysin messenger RNA was replicated when six subjects with schizophrenia not included in the earlier study were considered separately. We conclude that autoclaving renders formalin-fixed, paraffin wax-embedded sections of human brain suitable for quantitative in situ hybridization histochemistry. This has considerable implications, given the wider availability, better morphology and easier handling of fixed than frozen human brain tissue. Using this material, we confirmed the finding of decreased synaptophysin messenger RNA in the hippocampal formation in schizophrenia, furthering the evidence for synaptic pathology in this region in the disorder.
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PMID:Detection and quantification of hippocampal synaptophysin messenger RNA in schizophrenia using autoclaved, formalin-fixed, paraffin wax-embedded sections. 1043 Apr 74


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