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)

NMDA receptor antagonists can induce a schizophrenia-like psychosis, but the role of NMDA receptors in the pathophysiology of schizophrenia remains unclear. Expression patterns of mRNAs for five NMDA receptor subunits (NR1/NR2A-D) were determined by in situ hybridization in prefrontal, parieto-temporal, and cerebellar cortex of brains from schizophrenics and from neuroleptic-treated and nonmedicated controls. In the cerebral cortex of both schizophrenics and controls, mRNAs for NR1, NR2A, NR2B, and NR2D subunits were preferentially expressed in layers II/III, Va, and VIa, with much higher levels in the prefrontal than in the parieto-temporal cortex. Levels of mRNA for the NR2C subunit were very low overall. By contrast, the cerebellar cortex of both schizophrenics and controls contained very high levels of NR2C subunit mRNA, whereas levels for the other subunit mRNAs were very low, except NR1, for which levels were moderate. Significant alterations in the schizophrenic cohort were confined to the prefrontal cortex. Here there was a shift in the relative proportions of mRNAs for the NR2 subunit family, with a 53% relative increase in expression of the NR2D subunit mRNA. No comparable changes were found in neuroleptic-treated or untreated controls. These findings indicate regional heterogeneity of NMDA receptor subunit expression in human cerebral and cerebellar cortex. In schizophrenics, the alterations in expression of NR2 subunit mRNA in prefrontal cortex are potential indicators of deficits in NMDA receptor-mediated neurotransmission accompanying functional hypoactivity of the frontal lobes.
 ...
PMID:Selective alterations in gene expression for NMDA receptor subunits in prefrontal cortex of schizophrenics. 861 85

Glutamatergic dysfunction has been suggested as a possible substrate of the pathophysiology of schizophrenia. Of the multiple glutamate receptors, those most commonly implicated in schizophrenia are the ionotropic subtypes, the NMDA, AMPA, and kainate receptors. The expression of the glutamate receptors has been determined at multiple levels of gene expression in postmortem brain samples from schizophrenics and controls; while results have not been entirely consistent from study to study, several generalizations have emerged from this literature: (1) The AMPA receptor is abnormally decreased in expression in the schizophrenic hippocampus, involving decreased levels of subunit transcripts and protein levels, as well as binding sites, (2) similar changes are seen for kainate receptor expression in the hippocampus, and (3) the obligate NMDA receptor subunit, NMDAR1, may be abnormally expressed in some cortical regions in schizophrenia. These data support the hypothesis of abnormal glutamatergic neurotransmission involving the ionotropic glutamate receptors in schizophrenia.
 ...
PMID:Glutamate receptor expression in schizophrenic brain. 1071 55

Previously, we have reported alterations in thalamic NMDA receptor subunit and excitatory amino acid transporter expression in schizophrenia, consistent with the hypothesis that thalamic glutamatergic dysfunction may contribute to the pathophysiology of this illness. We have generalized this hypothesis to include other molecules of the glutamate synapse. Using riboprobes specific for human brain-specific Na+-dependent inorganic phosphate transporter (BNPi) and differentiation-associated Na+/Pi co-transporter (DNPi), both vesicular glutamate transporters, in situ hybridization was performed in the thalami of persons with schizophrenia and comparison subjects. We detected increased expression of DNPi mRNA in the thalamus in schizophrenia, while BNPi mRNA was not expressed in the thalamus in any subjects. These findings support the hypothesis of glutamatergic dysfunction in the thalamus in schizophrenia.
 ...
PMID:Vesicular glutamate transporter transcript expression in the thalamus in schizophrenia. 1158 96

Multiple neurotransmitter systems have been implicated in the pathophysiology of schizophrenia. Dopamine hyperactivity has often been implicated in this illness. More recently, the glutamate hypothesis of schizophrenia suggests that NMDA receptor (NMDAR) hypofunction may also play a role in this illness. This is based primarily on studies showing that phencyclidine, an NMDAR antagonist, can induce a schizophreniform psychosis. While NMDAR dysfunction is most often implicated in schizophrenia, other components of the glutamate system, such as the AMPA and kainate receptors, as well as NMDAR-associated intracellular proteins, may also play a role in regulating NMDA receptor activity and glutamate neurotransmission. There is growing interest in the hypothesis that the pathophysiology of schizophrenia involves alterations in dopamine-glutamate interactions. The glutamate system is anatomically and functionally linked to the dopamine system, and glutamate can modulate dopaminergic activity and release by stimulating various glutamate receptor subtypes expressed by dopaminergic neurons in the substantia nigra/ventral tegmental area. In this study, we investigated dopamine-glutamate interactions by measuring the expression of transcripts encoding the subunits for the ionotropic glutamate receptors (NMDA, AMPA and kainate) and five NMDAR-associated intracellular proteins, PSD-93, PSD-95, SAP102, NF-L and yotiao in the dopaminergic neurons in the substantia nigra pars compacta (SNc) of subjects with schizophrenia and a comparison group. Tyrosine hydroxylase (TH, a marker of dopamine-synthesizing cells), NR1 (an NMDA receptor subunit) and GluR5 (a kainate subunit) transcript levels were significantly increased in the SNc in schizophrenia. These data support the hypothesis that schizophrenia may involve alterations in dopamine-glutamate interactions.
 ...
PMID:Expression of the ionotropic glutamate receptor subunits and NMDA receptor-associated intracellular proteins in the substantia nigra in schizophrenia. 1496 37

Several lines of investigation support a hypothesis of glutamatergic dysfunction in schizophrenia, including our recent reports of altered NMDA receptor subunit and associated intracellular protein transcripts in the thalamus of elderly patients with schizophrenia. In the present study, we used in situ hybridization to measure the expression of NMDA subunits (NR1, NR2A-D), and associated intracellular proteins (NF-L, PSD95, and SAP102) in a second, younger cohort from the Stanley Foundation Neuropathology Consortium, which included patients with both schizophrenia and affective disorders. We wanted to determine whether glutamatergic abnormalities in the thalamus in schizophrenia are present at younger ages, and whether these abnormalities occur in other psychiatric illnesses. In the present work, we observed increased expression of NMDA NR2B subunit transcripts, and decreased expression of all three associated postsynaptic density protein transcripts in schizophrenia. We also found evidence of glutamatergic dysfunction in the thalamus in affective disorders, particularly in bipolar disorder. In particular, we found decreased NF-L, PSD95, and SAP102 transcripts in bipolar disorder, and decreased SAP102 levels in major depression. Interestingly, one of the most consistent findings across diagnostic groups was an abnormality of intracellular signaling molecules that are linked to the NMDA receptor, rather than changes in the receptor subunits themselves. PSD95 and similar scaffolding molecules link the NMDA receptor with intracellular enzymes that mediate signaling, and also provide a physical link between different neurotransmitter systems to coordinate and integrate information from multiple effector systems. Abnormalities of PSD95-like molecules and other intracellular signaling machinery may contribute to dysregulated communication between multiple neurotransmitter systems (such as glutamatergic and dopaminergic systems) that are potentially involved in the neurobiology of schizophrenia and affective disorders.
 ...
PMID:Abnormalities of the NMDA Receptor and Associated Intracellular Molecules in the Thalamus in Schizophrenia and Bipolar Disorder. 1505 76

Much interest has focussed on glutamate and the N-Methyl-D-Aspartate (NMDA) glutamate receptor in the pathogenesis of schizophrenia. A number of studies have reported abnormal gene transcription of various glutamate receptor subtypes in the hippocampus including the NMDA receptor. However, corresponding protein levels in subregions of the hippocampus have not yet been investigated. We have used immunoautoradiographical techniques to assess the expression of the obligatory NMDA receptor subunit NR1 and an associated post-synaptic density protein PSD-95 in the hippocampal dentate gyrus and orbitofrontal cortex (OFC) in schizophrenia and mood disorder. Optical density measures from film autoradiographs revealed no changes in NR1 or PSD-95 in the OFC or dentate hilus, however a decrease in PSD-95 was found in the dentate molecular layer in both schizophrenia and bipolar disorder relative to major depression. These findings were unrelated to antipsychotic or mood stabilizer drug treatment. The dentate molecular layer contains the dendritic trees of granule cells and is the target of major excitatory afferent inputs from associative cortical, parahippocampal and hippocampal regions. A reduction in PSD-95 at glutamate synapses of the molecular layer may have a deleterious impact on information flow to other hippocampal regions via granule cells and their projecting mossy fibres. A down-regulation of PSD-95 in schizophrenia and bipolar disorder may also relate to disease mechanisms of psychosis.
 ...
PMID:NMDA receptor subunit NRI and postsynaptic protein PSD-95 in hippocampus and orbitofrontal cortex in schizophrenia and mood disorder. 1614 May 6

D-Serine is an endogenous coagonist that increases the opening of N-methyl-D-aspartate (NMDA)-type glutamate receptor channels. We previously reported a reduction of D-serine serum levels in schizophrenia, supporting the disease hypothesis of NMDA receptor-mediated hypo-neurotransmission. The serum levels of D-serine are thought to reflect brain d-serine content. It is important to understand whether there is a direct link between the altered D-serine levels and NMDA receptor expression in vivo or whether these are independent processes. Two polymorphisms are known to regulate the expression of NMDA receptor subunit genes: (GT)(n) (rs3219790) in the promoter region of the NR2A subunit gene (GRIN2A) and -200T > G (rs1019385) in the NR2B gene (GRIN2B). These polymorphisms are also reported to be associated with schizophrenia. Therefore, we examined the correlation between these two polymorphisms and d-serine serum levels in mentally healthy controls, schizophrenics and the combined group. We observed no significant genotype-phenotype correlations in any of the sample groups. However, analyses of larger sample numbers and the detection of additional polymorphisms that affect gene expression are needed before we can conclude that NMDA receptor expression and serum levels of d-serine, if involved in schizophrenia pathophysiology, are independent and additive events.
 ...
PMID:Analysis of correlation between serum D-serine levels and functional promoter polymorphisms of GRIN2A and GRIN2B genes. 1626 83

Numerous studies have described structural and functional abnormalities of the thalamus in schizophrenia, but surprisingly few studies have examined neurochemical abnormalities that accompany these pathological changes. We previously identified abnormalities of multiple molecules associated with glutamatergic neurotransmission, including changes in NMDA receptor subunit transcripts and binding sites and NMDA receptor-associated post-synaptic density (PSD) protein transcripts in the thalamus of elderly patients with schizophrenia. In the present study, we performed western blot analysis to determine whether protein levels of NMDA receptor subunits (NR1, NR2A, NR2B) and associated PSD proteins (NF-L, PSD95, SAP102) are altered in schizophrenia. Thalamic tissue from each subject was grossly dissected into two regions: a dorsomedial region containing limbic-associated dorsomedial, anterior and central medial thalamic nuclei; and a ventral thalamus region that primarily consisted of the ventral lateral nucleus. We observed increased protein expression of the NR2B NMDA receptor subunit and its associated intracellular protein, PSD95, in the dorsomedial thalamus of patients with schizophrenia, but the other molecules were unchanged, and we found no changes in the ventral thalamus. These data provide additional evidence of thalamic neurochemical abnormalities, particularly in thalamic nuclei which project to limbic regions of the brain. Further, these findings provide additional evidence of NMDA receptor alterations in schizophrenia, which may play an important role in the neurobiology of the illness.
 ...
PMID:Up-regulation of NMDA receptor subunit and post-synaptic density protein expression in the thalamus of elderly patients with schizophrenia. 1676 23

The modulation of histamine neuron activity by various non-competitive NMDA-receptor antagonists was evaluated by changes in tele-methylhistamine (t-MeHA) levels and histidine decarboxylase (hdc) mRNA expression induced in rodent brain. The NMDA open-channel blockers phencyclidine (PCP) and MK-801 enhanced t-MeHA levels in mouse brain by 50-60%. Ifenprodil, which interacts with polyamine sites of NR2B-containing NMDA receptors, had no effect. PCP also increased hdc mRNA expression in the rat tuberomammillary nucleus. The enhancement of t-MeHA levels elicited by MK-801 (ED50 of approximately 0.1 mg/kg) was observed in the hypothalamus, cerebral cortex, striatum and hippocampus. Control t-MeHA levels and the t-MeHA response to MK-801 were not different in male and female mice. Double immunostaining for HDC and NMDA receptor subunits showed that histamine neurons of the rat tuberomammillary nucleus express NMDA receptor subunit 1 (NR1) with NMDA receptor subunit 2A (NR2A) and NMDA receptor 2B subunit (NR2B). In addition, immunoreactivity for the neuronal glutamate transporter EAAC1 was observed near most histaminergic perikarya. Hence, these findings support the existence of histamine/glutamate functional interactions in the brain. The increase in histamine neuron activity induced by NMDA receptor antagonists further suggests a role of histamine neurons in psychotic disorders. In addition, the decrease in MK-801-induced hyperlocomotion observed in mice after administration of ciproxifan further strengthens the potential interest of H3-receptor antagonist/inverse agonists for the symptomatic treatment of schizophrenia.
 ...
PMID:N-methyl-D-aspartate receptor antagonists enhance histamine neuron activity in rodent brain. 1692 61

In humans, phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, reproduces a schizophrenia-like psychosis including positive symptoms, negative symptoms and cognitive dysfunction. Thus, PCP-treated animals have been utilized as an animal model of schizophrenia. PCP-treated animals exhibit hyperlocomotion as an index of positive symptoms, and a social behavioral deficit in a social interaction test and enhanced immobility in a forced swimming test as indices of negative symptoms. They also show a sensorimotor gating deficit and cognitive dysfunctions in several learning and memory tests. Some of these behavioral changes endure after withdrawal from repeated PCP treatment. Furthermore, repeated PCP treatment induces some neurochemical and neuronanatomical changes. Recently, genetic approaches based on "the glutamate hypothesis of schizophrenia" have been used to develop animal models of schizophrenia. NMDA receptor subunit zeta1 knockdown, epsilon1 knockout (KO) and zeta1 point mutant mice exhibiting a hypofunction of NMDA receptors show hyperlocomotion, social behavioral deficit, sensorimotor gating deficit or cognitive dysfunction. Forebrain-specific calcineurin KO, neuregulin 1 heterozygous KO and lysophosphatidic acid 1 receptor KO mice can also serve as animal models of schizophrenia. These findings suggest that PCP and genetic animal models would be useful for evaluating novel therapeutic candidates and for confirming pathological mechanisms of schizophrenia.
 ...
PMID:Phencyclidine and genetic animal models of schizophrenia developed in relation to the glutamate hypothesis. 1760 43


1 2 3 Next >>