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)

The atypical antipsychotic drug clozapine effectively alleviates both negative and positive symptoms of schizophrenia via unclear cellular mechanisms. Clozapine may modulate both glutamatergic and dopaminergic transmission in the prefrontal cortex (PFC) to achieve part of its therapeutic actions. Using whole cell patch-clamp techniques, current-clamp recordings in layers V-VI pyramidal neurons from rat PFC slices showed that stimulation of local afferents (in 2 microM bicuculline) evoked mixed [AMPA/kainate and N-methyl-D-aspartate (NMDA) receptors] glutamate receptor-mediated excitatory postsynaptic potentials (EPSPs). Clozapine (1 microM) potentiated polysynaptically mediated evoked EPSPs (V(Hold) = -65 mV), or reversed EPSPs (rEPSP, V(Hold) = +20 mV) for >30 min. The potentiated EPSPs or rEPSPs were attenuated by elevating [Ca(2+)](O) (7 mM), by application of NMDA receptor antagonist 2-amino5-phosphonovaleric acid (50 microM), or by pretreatment with dopamine D1/D5 receptor antagonist SCH23390 (1 microM) but could be further enhanced by a dopamine reuptake inhibitor bupropion (1 microM). Clozapine had no significant effect on pharmacologically isolated evoked NMDA-rEPSP or AMPA-rEPSPs but increased spontaneous EPSPs without changing the steady-state resting membrane potential. Under voltage clamp, clozapine (1 microM) enhanced the frequency, and the number of low-amplitude (5-10 pA) AMPA receptor-mediated spontaneous EPSCs, while there was no such changes with the mini-EPSCs (in 1 microM TTX). Taken together these data suggest that acute clozapine can increase spike-dependent presynaptic release of glutamate and dopamine. The glutamate stimulates distal dendritic AMPA receptors to increase spontaneous EPSCs and enabled a voltage-dependent activation of neuronal NMDA receptors. The dopamine released stimulates postsynaptic D1 receptor to modulate a lasting potentiation of the NMDA receptor component of the glutamatergic synaptic responses in the PFC neuronal network. This sequence of early synaptic events induced by acute clozapine may comprise part of the activity that leads to later cognitive improvement in schizophrenia.
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PMID:Interaction of dopamine D1 and NMDA receptors mediates acute clozapine potentiation of glutamate EPSPs in rat prefrontal cortex. 1197 71

Schizophrenia is a severe psychiatric illness characterised by disturbance of thought, hallucination and delusions.(1) Several studies have suggested that dysfunctions in the glutamatergic transmission are linked to the pathogenesis of schizophrenia, and in particular an excessive activation of glutamate receptors seems to be related to the disruption of neuronal ionic gradients leading to excitotoxicity.(2-7) Numerous findings suggested that the kainate ionotropic glutamate receptors are primarily involved in this mechanism. Recently it has been demonstrated that the GRIK3 gene encoding for the ionotropic glutamate receptor kainate 3 contains a functional polymorphism (T928G) leading to the substitution of a serine with an alanine in position 310 of the protein sequence.(8-11) We performed an association study between the ser310ala GRIK3polymorphism and schizophrenia in a sample of 99 schizophrenic patients and 116 controls. We found a significant difference in the genotype distribution and in particular considering the ala allele as dominant (P = 0.0105, odds ratio (OR) 2.031, 95% confidence interval (CI) 1.177-3.504). This finding suggests a potential role for GRIK3 for susceptibility to schizophrenia.
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PMID:Association between the ionotropic glutamate receptor kainate 3 (GRIK3) ser310ala polymorphism and schizophrenia. 1198 86

The hippocampus is crucial for normal brain function, especially for the encoding and retrieval of multimodal sensory information. Neuropsychiatric disorders such as temporal lobe epilepsy, amnesia, and the dementias are associated with structural and functional abnormalities of specific hippocampal neurons. More recently we have also found evidence for a role of the hippocampus in the pathophysiology of schizophrenia. The most consistent finding is a subtle, yet significant volume difference in schizophrenia. Here we review the cellular and molecular basis of smaller hippocampal volume in schizophrenia. In contrast to neurodegenerative disorders, total hippocampal cell number is not markedly decreased in schizophrenia. However, the intriguing finding of a selective loss of hippocampal interneurons deserves further study. Two neurotransmitter receptors, the GABAA and AMPA/kainate glutamate receptors, appear to be abnormal, whereas changes of the NMDA glutamate receptor are less robust. The expression of several genes, including those related to the GABAergic system, neurodevelopment, and synaptic function, is decreased in schizophrenia. Taken together, recent studies of hippocampal cell number, protein expression, and gene regulation point towards an abnormality of hippocampal architecture in schizophrenia.
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PMID:Hippocampal neurons in schizophrenia. 1211 76

N-methyl-D-aspartate (NMDA) glutamate receptor antagonists are used in clinical anesthesia and are being developed as therapeutic agents for preventing neurodegeneration in stroke, epilepsy, and brain trauma. However, the ability of these agents to produce neurotoxicity in adult rats and psychosis in adult humans compromises their clinical usefulness. In addition, an NMDA receptor hypofunction (NRHypo) state might play a role in neurodegenerative and psychotic disorders, like Alzheimer's disease, bipolar disorder and schizophrenia. Thus, developing pharmacological means of preventing these NRHypo-induced effects could have significant clinically relevant benefits. NRHypo neurotoxicity appears to be mediated by a complex disinhibition mechanism that results in the excessive stimulation of certain vulnerable neurons. Here we report our findings that five agents (phenytoin, carbamazepine, valproic acid, lamotrigine, and riluzole), thought to possess anticonvulsant activity because they inhibit voltage-gated sodium channels, prevent NRHypo neurotoxicity. The ability of tetrodotoxin, a highly selective inhibitor of voltage-gated sodium channels, to prevent the same neurotoxicity suggests that inhibition of this ion channel is the likely mechanism of action of these five agents. We also found that three other anticonvulsants (felbamate, gabapentin and ethosuximide), whose mechanism is less clear, also prevent NRHypo neurotoxicity, suggesting that inhibition of voltage-gated sodium channels is not the only mechanism via which anticonvulsants can act to prevent NRHypo neurotoxicity. Several of these agents have been found to be of clinical use in bipolar disorder. It would be of interest to determine whether these agents might have therapeutic benefits for conditions in which a NRHypo state may exist.
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PMID:Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity. 1219 17

Receptor tyrosine kinases (RTKs) are membrane spanning proteins with intrinsic kinase activity. Although these receptors are known to be involved in proliferation and differentiation of cells, their roles in regulating central synaptic transmission are largely unknown. In CA1 pyramidal neurons, activation of D2 class dopamine receptors depressed excitatory transmission mediated by the NMDA subtype of glutamate receptor. This depression resulted from the quinpirole-induced release of intracellular Ca(2+) and enhanced Ca(2+)-dependent inactivation of NMDA receptors. The dopamine receptor-mediated depression was dependent on the "transactivation" of PDGFRbeta. Therefore, RTK transactivation provides a novel mechanism of communication between dopaminergic and glutamatergic systems and might help to explain how reciprocal changes in these systems could be linked to the deficits in cognition, memory, and attention observed in schizophrenia and attention deficit hyperactivity disorder.
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PMID:A D2 class dopamine receptor transactivates a receptor tyrosine kinase to inhibit NMDA receptor transmission. 1235

A map of 191 single-nucleotide polymorphism (SNPs) was built across a 5-Mb segment from chromosome 13q34 that has been genetically linked to schizophrenia. DNA from 213 schizophrenic patients and 241 normal individuals from Canada were genotyped with this marker set. Two 1,400- and 65-kb regions contained markers associated with the disease. Two markers from the 65-kb region were also found to be associated to schizophrenia in a Russian sample. Two overlapping genes G72 and G30 transcribed in brain were experimentally annotated in this 65-kb region. Transfection experiments point to the existence of a 153-aa protein coded by the G72 gene. This protein is rapidly evolving in primates, is localized to endoplasmic reticulum/Golgi in transfected cells, is able to form multimers and specifically binds to carbohydrates. Yeast two-hybrid experiments with the G72 protein identified the enzyme d-amino acid oxidase (DAAO) as an interacting partner. DAAO is expressed in human brain where it oxidizes d-serine, a potent activator of N-methyl-D-aspartate type glutamate receptor. The interaction between G72 and DAAO was confirmed in vitro and resulted in activation of DAAO. Four SNP markers from DAAO were found to be associated with schizophrenia in the Canadian samples. Logistic regression revealed genetic interaction between associated SNPs in vicinity of two genes. The association of both DAAO and a new gene G72 from 13q34 with schizophrenia together with activation of DAAO activity by a G72 protein product points to the involvement of this N-methyl-d-aspartate receptor regulation pathway in schizophrenia.
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PMID:Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. 1237 53

Stimulation of the dopamine (DA) system disrupts prepulse inhibition (PPI) of the acoustic startle response. On the basis of rat studies, it appeared that DA D2 receptors (D2Rs) rather than D1 receptors (D1Rs) regulate PPI, albeit possibly in synergism with D1Rs. To characterize the DA receptor modulation of PPI in another species, we tested DA D1R and D2R mutant mice with direct and indirect DA agonists and with the glutamate receptor antagonist, dizocilpine (MK-801). Neither the mixed D1/D2 agonist apomorphine (5 mg/kg) nor the more selective D1-like agonist SKF82958 (0.3 mg/kg) altered PPI in D1R knock-out mice, although both compounds disrupted PPI in D2R mutant and wild-type mice, suggesting that the D1R alone might modulate PPI in mice. However, amphetamine (10 mg/kg) significantly lowered PPI in each genotype of D1R mice, suggesting that the D1R is not necessary for the PPI-disruptive effect of the indirect agonist in mice. As reported previously, amphetamine (10 mg/kg) failed to disrupt PPI in D2R knock-out mice, supporting a unique role of the D2R in the modulation of PPI. Dizocilpine (0.3 mg/kg) induced similar PPI deficits in D1R and D2R mutant mice, confirming that the influences of the NMDA receptor on PPI are independent of D1Rs and D2Rs in rodents. Thus, both D1Rs and D2Rs modulate aspects of PPI in mice in a manner that differs from dopaminergic modulation in rats. These findings emphasize that further cross-species comparisons of the pharmacology of PPI are essential to understand the relevance of rodent PPI studies to the deficits in PPI observed in patients with schizophrenia.
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PMID:Differential effects of direct and indirect dopamine agonists on prepulse inhibition: a study in D1 and D2 receptor knock-out mice. 1241 85

The anterior cingulate cortex is a brain area of potential importance to our understanding of the pathophysiology of schizophrenia. Previous studies suggest abnormalities in the glutamatergic neurotransmission in the anterior cingulate cortex in schizophrenia patients. In the present study we used quantitative autoradiography to investigate the binding of [3H]MK801, [3H]L-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and [3H]kainate, which respectively label the N-methyl-D-aspartate (NMDA), AMPA, and kainate receptors of the ionotropic glutamate receptor family, in the left anterior cingulate cortex of 10 schizophrenia patients and 10 controls, matched for age, gender, and postmortem interval.AMPA receptor densities were higher in cortical layer II, whereas NMDA receptor densities were higher in cortical layers II-III in the anterior cingulate cortex of both control and schizophrenia group. In contrast, kainate receptors displayed the highest density in cortical layer V. [3H]AMPA binding was significantly increased by 25% in layer II in the schizophrenia group as compared with the control group. Similarly, a significant 17% increase of [3H]MK801 binding was observed in layers II-III in the schizophrenia group. No statistically significant difference was observed for [3H] kainate binding between the schizophrenia and control groups. These results suggest that ionotropic glutamate receptors are differentially altered in the anterior cingulate region in schizophrenia. The increase in [3H]AMPA and [3H]MK801 binding in the superficial layers suggests a postsynaptic compensation for impaired glutamatergic neurotransmission in the anterior cingulate cortex in schizophrenia. The findings add to a growing body of literature that supports a dysfunction of excitatory activity in the anterior cingulate cortex in schizophrenia.
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PMID:Selective alterations in ionotropic glutamate receptors in the anterior cingulate cortex in schizophrenia. 1243 56

Schizophrenia is a severe, complex mental disorder with unknown etiology. Abnormal glutamate neurotransmission has been proposed as one of the hypotheses of the pathogenesis of schizophrenia. Mohn recently reported that transgenic mice with the reduced glutamate receptor, ionotropic, -methyl-D-aspartate 1 gene (GRIN1) (formerly referred to as NMDAR1) expression display schizophrenia-like behaviors, which can be ameliorated by antipsychotic drug treatment. Their report promoted us to examine whether mutations in the human GRIN1 gene may convey genetic susceptibility to schizophrenia. To test this possibility, we systematically screened mutations in the promoter region and in all the exons of the human GRIN1 gene in a cohort of Chinese schizophrenic patients from Taiwan. Using single-strand conformation polymorphism analysis and autosequencing, we identified two single nucleotide polymorphisms, designated g.-1140G>A and g.-855G>C, respectively, at the 5'-untranslated region of the human GRIN1 gene. Genetic association study, however, revealed no association of these two single nucleotide polymorphisms with schizophrenia in our patients. Besides, no other mutations of the human GRIN1 gene were detected in this study. Our data suggest that the human GRIN1 gene may not contribute substantially to the genetic etiology of schizophrenia in our population.
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PMID:Systematic mutation analysis of the human glutamate receptor, ionotropic, N-methyl-D-aspartate 1 gene(GRIN1) in schizophrenic patients. 1245 27

Prenatal stress greatly influences the ability of an individual to manage stressful events in adulthood. Such vulnerability may result from abnormalities in the development and integration of forebrain dopaminergic and glutamatergic projections during the prenatal period. In this study, we assessed the effects of prenatal stress on the expression of selective dopamine and glutamate receptor subtypes in the adult offsprings of rats subjected to repeated restraint stress during the last week of pregnancy. Dopamine D2-like receptors increased in dorsal frontal cortex (DFC), medial prefrontal cortex (MPC), hippocampal CA1 region and core region of nucleus accumbens (NAc) of prenatally stressed rats compared to control subjects. Glutamate NMDA receptors increased in MPC, DFC, hippocampal CA1, medial caudate-putamen, as well as in shell and core regions of NAc. Group III metabotropic glutamate receptors increased in MPC and DFC of prenatally stressed rats, but remained unchanged in all other regions examined. These results indicate that stress suffered during the gestational period has long lasting effects that extend into the adulthood of prenatally stressed offsprings. Changes in dopamine and glutamate receptor subtype levels in different forebrain regions of adult rats suggest that the development and formation of the corticostriatal and corticolimbic pathways may be permanently altered as a result of stress suffered prenatally. Maldevelopment of these pathways may provide a neurobiological substrate for the development of schizophrenia and other idiopathic psychotic disorders.
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PMID:Long-term effects of prenatal stress on dopamine and glutamate receptors in adult rat brain. 1251 57

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