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)

The efficacy of antipsychotics in the treatment of schizophrenia depends on their ability to block dopamine (DA) D2 receptors. D2 receptor excitatory mediation of glutamatergic receptors has been implicated in in vivo studies. However, D2 receptor enhancement of glutamatergic transmission has rarely been reported in slice recordings. Instead, D2 receptor depression of both alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) action was obtained in previous slice studies. To obtain insight into this paradox, we examined DA's actions on synaptic responses of layer V pyramidal cells to minimal extracellular stimulation in layer III of ferret prefrontal cortical slices under NMDA and gamma-aminobutyric acid type A blockade. This experimental design models the proposed hypofunction of NMDA receptor and gamma-aminobutyric acid type A deficiency in schizophrenia. We found that DA and D2 receptor agonists promoted burst firing in a subset of pyramidal cells, which was reversed by haloperidol, a D2 antagonist and a D3 agonist, compounds having antipsychotic efficacy. In contrast, a D4 antagonist, which has not proven clinically effective, was not effective in blocking DA-promoted bursts. These results revealed excitatory effects of DA mediated mainly via D2 receptors, potentially providing a cellular mechanism for the D2 antagonism in treating schizophrenia.
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PMID:D2 receptor regulation of synaptic burst firing in prefrontal cortical pyramidal neurons. 1505 74

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

As quantitative neuroimaging continues to elucidate the gross neuropathology of schizophrenia, neurochemical and histological studies have contributed to defining this pathology in terms of neurotransmitter dysfunction. Increasingly, there is evidence implicating neurons containing the major inhibitory neurotransmitter of the brain--gamma-aminobutyric acid (GABA). Benes was the first to demonstrate deficits in some morphological subtypes of interneurons in the frontal cortex in schizophrenia. We identified that this was specific to a subgroup of GABAergic interneurons containing parvalbumin (PV), which is found in the fast-firing cells providing inhibitory control of the cortico-fugal pyramidal cells. PV is notable in being expressed late in development; the late expression of this protective calcium binding protein (CBP) may impart an early vulnerability to these neurons, indicating a possible mechanism for the developmental origins of schizophrenia. Cortical GABAergic neurons expressing the CBP calretinin (CR) are unaffected in schizophrenia, although those containing calbindin (CB) are also diminished in number. These deficits in PV and CB are notable in also being observed in bipolar disorder, indicating how the close aetiological relationship of these two psychiatric disorders is reflected in their pathology. One of the most substantial abnormalities seen in post-mortem brain tissue is the hippocampal deficit of PV-containing neurons, again in the absence of effects on CR-positive cells. This deficit occurring in a structure implicated in cognitive symptomatology may well have functional relevance, and we find it can be induced by a model of the disease, sub-chronic phencyclidine (PCP) administration, that can also produce cognitive disturbances. This PCP model, like schizophrenia, demonstrates other neurochemical changes which include indicators of glutamatergic dysfunction. The temporal and aetiological relationships between glutamatergic and GABAergic deficits remains unclear, but may well relate to an initial loss/dysfunction of GABA/PV neurons that subsequently gives rise to a glutamatergic pathology.
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PMID:Calcium binding protein markers of GABA deficits in schizophrenia--postmortem studies and animal models. 1518 6

Antiepileptic drugs (AEDs) are commonly prescribed for nonepileptic conditions, including migraine headache, chronic neuropathic pain, mood disorders, schizophrenia and various neuromuscular syndromes. In many of these conditions, as in epilepsy, the drugs act by modifying the excitability of nerve (or muscle) through effects on voltage-gated sodium and calcium channels or by promoting inhibition mediated by gamma-aminobutyric acid (GABA) A receptors. In neuropathic pain, chronic nerve injury is associated with the redistribution and altered subunit compositions of sodium and calcium channels that predispose neurons in sensory pathways to fire spontaneously or at inappropriately high frequencies, often from ectopic sites. AEDs may counteract this abnormal activity by selectively affecting pain-specific firing; for example, many AEDs suppress high-frequency action potentials by blocking voltage-activated sodium channels in a use-dependent fashion. Alternatively, AEDs may specifically target pathological channels; for example, gabapentin is a ligand of alpha2delta voltage-activated calcium channel subunits that are overexpressed in sensory neurons after nerve injury. Emerging evidence suggests that effects on signaling pathways that regulate neuronal plasticity and survival may be a factor in the delayed clinical efficacy of AEDs in some neuropsychiatric conditions, including bipolar affective disorder.
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PMID:The neurobiology of antiepileptic drugs for the treatment of nonepileptic conditions. 1522 16

A number of investigations have provided a growing body of evidence of the involvement of the gamma-aminobutyric acid (GABA) transmitter system in the pathophysiology of schizophrenia and bipolar disorder. In this study, immunohistochemical and immunoblot techniques were employed in order to examine alterations of the GABA(A) receptor alpha1 and beta2/3 subunits in the prefrontal cortex from postmortem subjects with schizophrenia and bipolar disorder. alpha1 immunoreactivity was observed in the neuropil of the prefrontal cortex and in the neuronal soma in specimens from both groups, as well as from normal controls. alpha1 immunolabeling in the neuronal soma from the schizophrenic group was more intense than that of the other two groups. The distribution of beta2/3 immunoreactivity was similar to that of alpha1. beta2/3 immunolabeling in the neuronal soma from the schizophrenia and bipolar disorder groups was more intense than that of the normal controls. The densitometry measurements, as well as the immunoblot analysis for alpha1 and beta2/3 were highly consistent with the alpha1 and beta2/3 immunohistochemistry results. The present study suggests that the expression of these two GABA(A) receptor subunits was altered in subjects with schizophrenia and bipolar disorder, but that the patterns of change differed between those with these two disorders.
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PMID:Immunohistochemical and immunoblot study of GABA(A) alpha1 and beta2/3 subunits in the prefrontal cortex of subjects with schizophrenia and bipolar disorder. 1528 1

While abnormalities of the prefrontal cortex and temporal lobe structures have typically been associated with the pathophysiology of schizophrenia, recent findings implicate thalamic dysfunction in this illness as well. The thalamus plays a critical role in processing and integrating sensory information relevant to emotional and cognitive functions. Neuropathological and in vivo imaging studies in schizophrenia have identified several structural and metabolic abnormalities in the thalamus, which may contribute to a deficit in sensory processing and be related to psychotic symptomatology. In addition to these postmortem and in vivo imaging studies indicating structural and metabolic changes in the thalamus in schizophrenia, more recent studies have examined the neurochemical substrates that accompany these changes. Much of this work to date has focused on glutamatergic abnormalities in the thalamus, in part because it is a predominant neurotransmitter used in the thalamus, and because glutamatergic dysfunction has been hypothesized to be involved in schizophrenia. Several studies, however, have also examined markers of gamma-aminobutyric acid (GABA) and dopaminergic neurotransmission in the thalamus in schizophrenia. We review these neurochemical findings, as well as the growing body of postmortem and in vivo imaging evidence that supports the hypothesis of thalamic dysfunction in schizophrenia.
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PMID:Thalamic dysfunction in schizophrenia: neurochemical, neuropathological, and in vivo imaging abnormalities. 1546 96

Postmortem brain studies have shown deficits in the cortical gamma-aminobutyric acid (GABA) system in schizophrenic individuals. Expression studies have shown a decrease in the major GABA-synthesizing enzyme (glutamic acid decarboxylase (GAD67) mRNA levels in neurons in dorsolateral prefrontal cortex in schizophrenics relative to controls. In the present study, SNPs in and around the GAD1 gene, which encodes the protein GAD67, were tested on a rare, severely ill group of children and adolescents with childhood-onset schizophrenia (COS) (n=72), in a family-based association analysis. Compared to adult-onset samples, the COS sample has evidence for more salient familial, and perhaps genetic, risk factors for schizophrenia, as well as evidence for frontal cortical hypofunction, and greater decline in cortical gray matter volume on anatomic brain MRI scans during adolescence. We performed family-based TDT and haplotype association analyses of the clinical phenotype, as well as association analyses with endophenotypes using the QTDT program. Three adjacent SNPs in the 5' upstream region of GAD1 showed a positive pairwise association with illness in these families (P=0.022-0.057). Significant transmission distortion of 4-SNP haplotypes was also observed (P=0.003-0.008). Quantitative trait TDT analyses showed an intriguing association between several SNPs and increased rate of frontal gray matter loss. These observations, when taken together with the positive results reported recently in two independent adult-onset schizophrenia pedigree samples, suggest that the gene encoding GAD67 may be a common risk factor for schizophrenia.
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PMID:GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss. 1550 39

Dehydroepiandrosterone has been recently recognized as neuroactive steroid with several vital neurophysiological activities on membrane receptors, such as N-methyl-d-aspartate, and gamma-aminobutyric acid receptors and on genomic androgen receptors. DHEA does also have an antiglucocorticoid effect. So far, the relevance of this neuroactive steroid to psychiatric disorders is not well known. In this study, plasma levels of DHEA were determined with a highly sensitive and specific gas-chromatography/mass-spectrometry method in 23 outpatients suffering from Diagnostic and Statistical Manual of Mental Disorders-IV schizophrenia compared with 23 healthy control subjects matched for age and sex. Plasma levels of DHEA were found to be strongly elevated in the group of schizophrenic patients (mean+/-SD=90.9+/-61.4 nmol/l) compared to that of control subjects (mean+/-SD=24.0+/-17.9 nmol/l) and the difference was highly significant (t=5.018, df=44, p<0.0001). This statistically significant difference was also found when we divided the groups of schizophrenics and controls in subgroups of males (t=4.536, df=24, p=0.0001) and females (t=2.777, df=18, p=0.0124). These results suggest that DHEA may have some role in the pathophysiology of schizophrenia due to its complex mechanism of action in the brain involving genomic and non-genomic components. Therefore, its study may provide further understanding of the pathophysiology of psychoses and open new avenues for their treatment.
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PMID:Plasma dehydroepiandrosterone levels are strongly increased in schizophrenia. 1641 63

Psychostimulant use disorder and schizophrenia have a substantial genetic basis. Evidence from human and animal studies on the involvement of the gamma-aminobutyric acid (GABA) system in methamphetamine (METH) use disorder and schizophrenia is mounting. As we tested for the association of the human GABA(A) receptor gamma 2 subunit gene (GABRG2) with each diagnostic group, we used a case-control design with a set of 178 subjects with METH use disorder, 288 schizophrenics and 288 controls. First, we screened 96 controls and identified six SNPs in GABRG2, three of whom we newly reported. Next, we selected two SNPs, 315C>T and 1128+99C>A, as representatives of the linkage disequilibrium blocks for further case-control association analysis. Although no associations were found in either allelic or genotypic frequencies, we detected a haplotypic association in GABRG2 with METH use disorder, but not with schizophrenia. This finding partly replicates a recent case-control study of GABRG2 in METH use disorder, and thus indicates that GABRG2 may be one of the susceptibility genes of METH use disorder.
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PMID:Haplotype association between GABAA receptor gamma2 subunit gene (GABRG2) and methamphetamine use disorder. 1577 96

Impairments in certain cognitive functions, such as working memory, are core features of schizophrenia. Convergent findings indicate that a deficiency in signalling through the TrkB neurotrophin receptor leads to reduced GABA (gamma-aminobutyric acid) synthesis in the parvalbumin-containing subpopulation of inhibitory GABA neurons in the dorsolateral prefrontal cortex of individuals with schizophrenia. Despite both pre- and postsynaptic compensatory responses, the resulting alteration in perisomatic inhibition of pyramidal neurons contributes to a diminished capacity for the gamma-frequency synchronized neuronal activity that is required for working memory function. These findings reveal specific targets for therapeutic interventions to improve cognitive function in individuals with schizophrenia.
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PMID:Cortical inhibitory neurons and schizophrenia. 1580 62


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