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

1. The glycine-binding site of the glutamatergic N-methyl-d-aspartate receptor subtype (NMDAr) has been proposed as a putative target for treating cognitive impairments in neurodegenerative disorders and schizophrenia. Although behavioural evidence has been accumulated showing that the partial agonist d-cycloserine (DCS) facilitated learning and memory, physiological mechanisms of the drug still remained to be characterized. In the present study, we have investigated the effects of DCS on glutamatergic neurotransmission and synaptic plasticity in CA1 region of rat hippocampal slices, using extracellular field excitatory postsynaptic potentials. 2. We showed that DCS facilitated NMDAr-mediated synaptic potentials. In addition, we found that the magnitude of NMDAr-dependent long-term depression was significantly enhanced by the agonist, while the threshold for the induction of lasting potentiations was lowered. 3. We found that DCS decreased neurotransmission mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate subtypes of glutamate receptors. This inhibition was not prevented by the gamma-aminobutyric acid GABAA antagonist bicuculline, but was antagonized by the glycine antagonist strychnine. 4. These results, therefore, show opposite effects of DCS on NMDA and non-NMDA synaptic responses within the hippocampus. They also demonstrate that DCS facilitates long-term synaptic plasticity that may support the DCS-induced enhanced cognitive performances.
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PMID:D-cycloserine facilitates synaptic plasticity but impairs glutamatergic neurotransmission in rat hippocampal slices. 1453 Feb 8

Post-weaning social isolation of rats produces psychological and physiological changes that are relevant to schizophrenia. Here, we report that long-term potentiation (LTP) in the CA1 to subiculum pathway is lower by 34%, (P<0.0001) in brain slices from isolates compared with those from socially housed rats. We also report that LTP in this pathway is NMDA receptor-dependent.
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PMID:Post-weaning social isolation of rats leads to a diminution of LTP in the CA1 to subiculum pathway. 1457 4

The molecular and neuronal substrates conferring on clozapine its unique and superior efficacy in the treatment of schizophrenia remain elusive. The interaction of clozapine with many G protein-coupled receptors is well documented but less is known about its biologically active metabolite, N-desmethylclozapine. Recent clinical and preclinical evidences of the antipsychotic activity of the muscarinic agonist xanomeline prompted us to investigate the effects of N-desmethylclozapine on cloned human M1-M5 muscarinic receptors. N-desmethylclozapine preferentially bound to M1 muscarinic receptors with an IC50 of 55 nM and was a more potent partial agonist (EC50, 115 nM and 50% of acetylcholine response) at this receptor than clozapine. Furthermore, pharmacological and site-directed mutagenesis studies suggested that N-desmethylclozapine preferentially activated M1 receptors by interacting with a site that does not fully overlap with the acetylcholine orthosteric site. As hypofunction of N-methyl-d-aspartate (NMDA) receptor-driven neuronal ensembles has been implicated in psychotic disorders, the neuronal activity of N-desmethylclozapine was electrophysiologically investigated in hippocampal rat brain slices. N-desmethylclozapine was shown to dose-dependently potentiate NMDA receptor currents in CA1 pyramidal cells by 53% at 100 nM, an effect largely mediated by activation of muscarinic receptors. Altogether, our observations provide direct evidence that the brain penetrant metabolite N-desmethylclozapine is a potent, allosteric agonist at human M1 receptors and is able to potentiate hippocampal NMDA receptor currents through M1 receptor activation. These observations raise the possibility that N-desmethylclozapine contributes to clozapine's clinical activity in schizophrenics through modulation of both muscarinic and glutamatergic neurotransmission.
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PMID:N-desmethylclozapine, an allosteric agonist at muscarinic 1 receptor, potentiates N-methyl-D-aspartate receptor activity. 1459 31

Postmortem studies, using various methods and directed at several molecular targets, have provided increasing evidence that glutamatergic neurotransmission is affected in schizophrenia. The bulk of the data are in the hippocampus, wherein there is reduced expression of one or more subunits for all three ionotropic receptors (NMDA, AMPA, and kainate). Presynaptic glutamatergic markers, notably the vesicular glutamate transporter VGLUT1, may also be decreased in schizophrenia, especially in older subjects. CA1 appears less affected than other subfields, and the decrements may be greater in the left than in the right hippocampus. The recently described susceptibility genes for schizophrenia all act upon glutamatergic synaptic transmission, which may, therefore, be part of the core pathophysiology of the disorder.
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PMID:Glutamate receptors and transporters in the hippocampus in schizophrenia. 1468 37

The information transfer from the superficial layers of the entorhinal cortex (EC) to the hippocampus is regulated in a frequency dependent manner. Phencyclidine and related compounds such as MK-801 produce psychotic symptoms that closely resemble schizophrenia. We studied the effects of systemic administration of MK-801 on the signal transfer from the EC layer III to the hippocampal area CA1. High frequency (above 10 Hz) activation of the bi-synaptic entorhinal input in control animals results in a strong suppression of the field potentials in the stratum lacunosum-moleculare of the area CA1. In contrast, in MK-801 pretreated rats the field response was less reduced. The field potential responses evoked in these two groups of animals by high-frequency activation of the monosynaptic input were similar suggesting selective alterations in layer III of the medial EC. We suggest, that MK-801 causes disinhibition of layer III projection cells and, therefore, may cause strong, pathological activation of direct layer III-CA1 pathway.
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PMID:Effects of phencyclidines on signal transfer from the entorhinal cortex to the hippocampus in rats. 1470 Jul 27

There is an increased incidence of schizophrenia-like psychosis in temporal lobe epilepsy (TLE), and several risk factors have been implicated, including the duration of epilepsy and temporal lobe neuropathology. To investigate the biological mechanism of epileptic psychosis, we examined alterations of central dopaminergic systems in the kainate model of TLE. In adult rats, kainate was microinjected into the left amygdala to induce status epilepticus. An indirect dopamine agonist methamphetamine (MAP, 2 mg/kg, i.p.) was administered before and 1 month after the kainate treatment. MAP-induced locomotor activity was significantly enhanced in the kainate group compared with the baseline (pre-kainate) level, which was antagonized by pretreatment with haloperidol. The enhancement of locomotor activity in the kainate group was significantly correlated with the density of hippocampal CA1 neurons. Although the basal extracellular dopamine concentration was significantly lower in the striatum in the kainate group than in the control group (5.5 vs 39.2 fmol/20-min sample), the maximal concentration following MAP administration did not differ between the two groups. These results clearly demonstrate that hypersensitivity of the dopamine systems develops in the chronic phase of the kainate-induced TLE model, which may be responsible for the mechanism of epileptic psychosis.
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PMID:Enhancement of central dopaminergic activity in the kainate model of temporal lobe epilepsy: implication for the mechanism of epileptic psychosis. 1503 65

Hippocampal volume reductions are widely observed in schizophrenia. Some studies suggest anterior hippocampal regions are more susceptible and associated with frontal lobe dysfunctions, while others implicate posterior regions. Using high-resolution MR images and novel computational image analysis methods, we identified the hippocampal subregions most vulnerable to disease processes in 62 (45 m/17 f) first-episode schizophrenia patients compared to 60 (30 m/30 f) healthy controls, similar in age. The hippocampi were traced on coronal brain slices and hemispheric volumes were compared between diagnostic groups. Regional structural abnormalities were identified by comparing distances, measured from homologous hippocampal surface points to the central core of each individual's hippocampal surface model, between groups in 3D. CSF concentrations were also compared statistically at homologous hippocampal surface points to localize corresponding gray matter reductions. Significant bilateral hippocampal volume reductions were observed in schizophrenia irrespective of brain size corrections. Statistical mapping results, confirmed by permutation testing, showed pronounced left hemisphere shape differences in anterior and midbody CA1 and CA2 regions in patients. Significant CSF increases surrounding the hippocampus were observed in a similar spatial pattern in schizophrenia. Results confirm that hippocampal volume reductions are a robust neuroanatomical correlate of schizophrenia and are present by first episode. Mid- to antero-lateral hippocampal regions show pronounced volume changes and complementary increases in peri-hippocampal CSF, suggesting that these hippocampal regions are more susceptible to disease processes in schizophrenia. Targeting regional hippocampal abnormalities may help dissociate schizophrenia patients from other groups exhibiting global hippocampal volume changes, and better focus systems-level pathophysiological hypotheses.
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PMID:Regional specificity of hippocampal volume reductions in first-episode schizophrenia. 1505 May 80

The growth factor neuregulin 1 (NRG1) has been proposed to contribute to the formation and maturation of neuromuscular and interneuronal synapses by upregulating the expression of specific neurotransmitter receptor subunits. In the present report, we show that, in the hippocampus, NRG1 is expressed in a pattern suggesting that it regulates synapse development in the CA1 region. However, in contrast to what has been shown in other synapses, NRG1 reduces the expression of gamma-aminobutyric acid (GABA)A receptors alpha subunits in hippocampal slices, and the mean amplitude of GABAergic miniature inhibitory postsynaptic currents (IPSCs) in hippocampal CA1 pyramidal neurons, without affecting IPSC kinetics or frequency. These effects of NRG1 occur without concomitant changes in glutamate receptors and other synaptic proteins. We propose that the role of NRG1 in the formation and maturation in the hippocampal inhibitory synapse is downregulation, rather than upregulation, of receptor subunit expression. These results suggest that NRG1 may contribute to the reduction in GABAergic synaptic activity in hippocampal CA1 pyramidal neurons that normally occurs during early postnatal development, and that alterations in NRG1 signaling in the hippocampus may contribute to schizophrenia and epilepsy.
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PMID:Neuregulin1 downregulates postsynaptic GABAA receptors at the hippocampal inhibitory synapse. 1513 33

It has been postulated that endogenous kynurenic acid (KYNA) modulates alpha7* nicotinic acetylcholine receptor (nAChR) and NMDA receptor activities in the brain.a To test this hypothesis, alpha7* nAChR and NMDA receptor functions were studied in mice with a targeted null mutation in the gene encoding kynurenine aminotransferase II (mKat-2-/- mice), an enzyme responsible for brain KYNA synthesis. At 21 postnatal days, mKat-2-/- mice had lower hippocampal KYNA levels and higher spontaneous locomotor activity than wild-type (WT) mice. At this age, alpha7* nAChR activity induced by exogenous application of agonists to CA1 stratum radiatum interneurons was approximately 65% higher in mKat-2-/- than WT mice. Binding studies indicated that the enhanced receptor activity may not have resulted from an increase in alpha7* nAChR number. In 21-d-old mKat-2-/- mice, endogenous alpha7* nAChR activity in the hippocampus was also increased, leading to an enhancement of GABAergic activity impinging onto CA1 pyramidal neurons that could be reduced significantly by acute exposure to KYNA (100 nM). The activities of GABA(A) and NMDA receptors in the interneurons and of alpha3beta4* nAChRs regulating glutamate release onto these neurons were comparable between mKat-2-/- and WT mice. By 60 d of age, KYNA levels and GABAergic transmission in the hippocampus and locomotor activity were similar between mKat-2-/- and WT mice. Our findings that alpha7* nAChRs are major targets for KYNA in the brain may provide insights into the pathophysiology of schizophrenia and Alzheimer's disease, disorders in which brain KYNA levels are increased and alpha7* nAChR functions are impaired.
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PMID:Targeted deletion of the kynurenine aminotransferase ii gene reveals a critical role of endogenous kynurenic acid in the regulation of synaptic transmission via alpha7 nicotinic receptors in the hippocampus. 1514 Sep 35

This paper puts the case for the hippocampus as being central to the neuropathology and pathophysiology of schizophrenia. The evidence comes from a range of approaches, both in vivo (neuropsychology, structural and functional imaging) and post mortem (histology, morphometry, gene expression, and neurochemistry). Neuropathologically, the main positive findings concern neuronal morphology, organisation, and presynaptic and dendritic parameters. The results are together suggestive of an altered synaptic circuitry or "wiring" within the hippocampus and its extrinsic connections, especially with the prefrontal cortex. These changes plausibly represent the anatomical component of the aberrant functional connectivity that underlies schizophrenia. Glutamatergic pathways are prominently but not exclusively affected. Changes appear somewhat greater in the left hippocampus than the right, and CA1 is relatively uninvolved compared to other subfields. Hippocampal pathology in schizophrenia may be due to genetic factors, aberrant neurodevelopment, and/or abnormal neural plasticity; it is not due to any recognised neurodegenerative process. Hippocampal involvement is likely to be associated with the neuropsychological impairments of schizophrenia rather than with its psychotic symptoms.
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PMID:The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications. 1520 86


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