UMLS:C0036341 - FACTA Search

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 type A gamma-aminobutyric acid (GABA(A)) receptors mediate the majority of fast inhibitory neurotransmission in the CNS, and alterations in GABA(A) receptor function is believed to be involved in the pathology of several neurological and psychiatric illnesses, such as epilepsy, anxiety, Alzheimer's disease, and schizophrenia. GABA(A) receptors can be assembled from eight distinct subunit families defined by sequence similarity: alpha(1-6), beta(1-3), gamma(1-3), delta, pi, theta, and rho(1-3). The regulation of GABA(A) receptor function in the brain is a highly compensating system, influencing both the number and the composition of receptors at the cell surface. While transcriptional and translational points of control operate in parallel, it is becoming increasingly evident that many functional changes in GABA(A) receptors reflect the differential gene regulation of its subunits. The fact that certain GABA(A) receptor subunit genes are transcribed in distinct cell types during specific periods of development strongly suggests that genetic control plays a major role in the choice of subunit variants available for receptor assembly. This review focuses on the physiological conditions that alter subunit mRNA levels, the promoters that may control such levels, and the use of a conceptual framework created by bioinformatics to study coordinate and independent GABA(A) receptor subunit gene regulation. As this exciting field moves closer to identifying the language hidden inside the chromatin of GABA(A) receptor subunit gene clusters, future experiments will be aimed at testing models generated by computational analysis with biologically relevant in vivo and in vitro assays. It is hoped that through this functional genomic approach there will be the identification of new targets for therapeutic intervention.
...
PMID:GABAA receptors: building the bridge between subunit mRNAs, their promoters, and cognate transcription factors. 1503 Oct 2

Prepulse inhibition (PPI) refers to the phenomenon in which a low-intensity prepulse stimulus attenuates the reflexive response to a succeeding startle-eliciting pulse stimulus. The hippocampus, among other structures, is believed to play an important role in the modulation of PPI expression. In alpha5(H105R) mutant mice, the expression of the alpha5 subunit-containing GABA(A) receptors in the hippocampus is reduced. Here, we report that PPI was attenuated, and spontaneous locomotor activity was increased in alpha5(H105R) mutant mice. These effects were apparent in both genders. Thus, alpha5 subunit-containing GABA(A) receptors, which are located extrasynaptically and are thought to mediate tonic inhibition, are important regulators of the expression of PPI and locomotor exploration. Post-mortem analyses of schizophrenia brains have consistently revealed structural abnormalities of a developmental origin in the hippocampus. There may be a possibility that such abnormalities include disturbance of alpha5 GABA(A) receptor function or distribution, given that schizophrenia patients are known to exhibit a PPI deficit. Our data further highlight that the potential use of alpha5-selective inverse agonists to treat hippocampal-related mnemonic dysfunction needs to be considered against the possibility that such compounds may be adversely associated with deficient sensorimotor gating.
...
PMID:Hippocampal alpha5 subunit-containing GABAA receptors modulate the expression of prepulse inhibition. 1526 4

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.
...
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

Glutamate-containing pyramidal neurons in the medial prefrontal cortex (mPfc) project to the ventral tegmental area (VTA) where they synapse on mesocorticolimbic dopamine containing cell bodies and GABA interneurons. In the present study we employed dual probe microdialysis in intact conscious rat brain to investigate the effects of intra-mPfc perfusion with a depolarising concentration of potassium chloride (KCl) (100 mM, 20 min) alone and in the presence of local GABA(A) and GABA(B) receptor blockade on VTA glutamate release. Intra-mPfc KCl transiently increased VTA glutamate release (+71.48+/-14.29%, 20 min). Intra-mPfc perfusion with a concentration of the GABA(A) receptor antagonist bicuculline (10 microM, 120 min) did not influence the intra-mPfc KCl-induced increase in VTA glutamate release (+102.35+/-33.61%, 20 min). In contrast, intra-mPfc perfusion with a concentration of the GABA(B) receptor antagonist CGP35348 (100 microM, 120 min) which when given alone did not influence basal glutamate levels in the VTA was associated with an enhanced KCl-induced stimulation of VTA glutamate release (+375.19+/-89.69%, 40 min). Furthermore, this enhancement was reversed in the presence of the selective GABA(B) receptor agonist baclofen (10 microM, 120 min). The present findings suggest a key role for the prefrontal cortex in the regulation of glutamate release in the VTA. Furthermore, we demonstrate a selective cortical GABA(B) receptor-mediated inhibition of glutamate transmission in the VTA. These findings may be important in the context of abnormalities in amino acid neurotransmission at the network level in schizophrenia.
...
PMID:Evidence for a selective prefrontal cortical GABA(B) receptor-mediated inhibition of glutamate release in the ventral tegmental area: a dual probe microdialysis study in the awake rat. 1556 37

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.
...
PMID:Haplotype association between GABAA receptor gamma2 subunit gene (GABRG2) and methamphetamine use disorder. 1577 96

Postmortem CNS studies have suggested an uncoupling of the gamma-aminobutyric acid (GABA) and benzodiazepine binding sites on the hippocampal GABA(A) receptor in schizophrenia. The GABA(A) receptor is an assembly of discrete subunits that form a ligand-gated ion channel, the binding characteristics of which are defined by receptor subunit composition. Thus, a likely explanation for an uncoupling between the GABA and benzodiazepine binding sites on the GABA(A) receptor would be a change in receptor subunit composition. To test this hypothesis we measured the density of GABA ([(3)H]muscimol) and benzodiazepine ([(3)H]flumazenil) binding sites on the GABA(A) receptor in hippocampi, obtained postmortem, from schizophrenic, bipolar I disorder and control subjects. In addition, we measured the amount of [(3)H]flumazenil binding that could be displaced with zolpidem and clonazepam. Levels of both [(3)H]muscimol and [(3)H]flumazenil binding were significantly decreased in part of the CA2 from subjects with schizophrenia; the decrease in [(3)H]flumazenil being due to decreases in both zolpidem-sensitive and -insensitive radioligand binding. There were complex regionally specific changes in [(3)H]muscimol binding in the hippocampus from subjects with bipolar I disorder but there were no significant changes in the overall levels of [(3)H]flumazenil binding. There were significant decreases in zolpidem-sensitive and increases in zolpidem-insensitive [(3)H]flumazenil binding in most regions of the sections of the hippocampal formation studied in bipolar I disorder. Unlike [(3)H]flumazenil, zolpidem does not bind to the alpha5 subunit of the GABA(A) receptor; therefore, we postulate that there is an increase in GABA(A) receptors containing alpha5 subunit in the hippocampus from subjects with bipolar I disorder.
...
PMID:Changes in hippocampal GABAA receptor subunit composition in bipolar 1 disorder. 1595 Mar 12

The main inhibitory neurotransmitter system in the brain, the gamma-aminobutyric acid (GABA) system, is the target for many clinically used drugs to treat, for example, anxiety disorders and epilepsy and to induce sedation and anesthesia. These drugs facilitate the function of pentameric A-type GABA (GABA(A)) receptors that are extremely widespread in the brain and composed from the repertoire of 19 subunit variants. Modern genetic studies have found associations of various subunit gene polymorphisms with neuropsychiatric disorders, including alcoholism, schizophrenia, anxiety, and bipolar affective disorder, but these studies are still at their early phase because they still have failed to lead to validated drug development targets. Recent neurobiological studies on new animal models and receptor subunit mutations have revealed novel aspects of the GABA(A) receptors, which might allow selective targeting of the drug action in receptor subtype-selective fashion, either on the synaptic or extrasynaptic receptor populations. More precisely, the greatest advances have occurred in the clarification of the molecular and behavioral mechanisms of action of the GABA(A) receptor agonists already in the clinical use, such as benzodiazepines and anesthetics, rather than in the introduction of novel compounds to clinical practice. It is likely that these new developments will help to overcome the present problems of the chronic treatment with nonselective GABA(A) agonists, that is, the development of tolerance and dependence, and to focus the drug action on the neurobiologically and neuropathologically relevant substrates.
...
PMID:GABA(A) receptor subtypes as targets for neuropsychiatric drug development. 1599 46

Overactivity of the dopaminergic system in the brain is considered to be a contributing factor to the development and symptomatology of schizophrenia. Therefore, the GABAergic control of dopamine functions was assessed by disrupting the gene encoding the alpha3 subunit of the GABA(A) receptor. alpha3 knockout (alpha3KO) mice exhibited neither an obvious developmental defect nor apparent morphological brain abnormalities, and there was no evidence for compensatory up-regulation of other major GABA(A)-receptor subunits. Anxiety-related behavior in the elevated-plus-maze test was undisturbed, and the anxiolytic-like effect of diazepam, which is mediated by alpha2-containing GABA(A) receptors, was preserved. As a result of the loss of alpha3 GABA(A) receptors, the GABA-induced whole-cell current recorded from midbrain dopamine neurons was significantly reduced. Spontaneous locomotor activity was slightly elevated in alpha3KO mice. Most notably, prepulse inhibition of the acoustic startle reflex was markedly attenuated in the alpha3KO mice, pointing to a deficit in sensorimotor information processing. This deficit was completely normalized by treatment with the antipsychotic D2-receptor antagonist haloperidol. The amphetamine-induced hyperlocomotion was not altered in alpha3KO mice compared with WT mice. These results suggest that the absence of alpha3-subunit-containing GABA(A) receptors induces a hyperdopaminergic phenotype, including a severe deficit in sensorimotor gating, a common feature among psychiatric conditions, including schizophrenia. Hence, agonists acting at alpha3-containing GABA(A) receptors may constitute an avenue for an effective treatment of sensorimotor-gating deficits in various psychiatric conditions.
...
PMID:A schizophrenia-related sensorimotor deficit links alpha 3-containing GABAA receptors to a dopamine hyperfunction. 1628 44

The superior temporal gyrus (STG) is strongly implicated in the pathophysiology of schizophrenia, particularly with regards to auditory hallucinations. In a previous study we reported a decrease in the density of M1 and M2/M4 muscarinic receptors in the STG in schizophrenia. In this study, we investigated the density of GABA(A) receptors in the left STG of schizophrenia patients compared to control subjects. We used quantitative autoradiography to investigate the binding of the agonist [(3)H] muscimol to GABA(A )receptors in the STG. A significantly higher density of [(3)H] muscimol binding was observed in the upper three quarters of the STG grey matter (corresponding to layers I-IV) than in the lower one-quarter (layers V-VI) in both groups. A significant increase (about 30%, P<0.05) in binding of [(3)H] muscimol was clearly observed in schizophrenia patients compared to control subjects. There were no significant correlations between [(3)H] muscimol binding density and age, post-mortem interval, brain pH or final recorded antipsychotic drug use. These results suggest an increase of GABA(A) receptor densities in the STG of schizophrenia patients.
...
PMID:Increased density of GABAA receptors in the superior temporal gyrus in schizophrenia. 1636 64

Because of its control of spike-timing and oscillatory network activity, gamma-aminobutyric acid (GABA)-ergic inhibition is a key element in the central regulation of somatic and mental functions. The recognition of GABA(A) receptor diversity has provided molecular tags for the analysis of distinct neuronal networks in the control of specific pharmacological and physiological brain functions. Neurons expressing alpha(1)GABA(A) receptors have been found to mediate sedation, whereas those expressing alpha(2)GABA(A) receptors mediate anxiolysis. Furthermore, associative temporal and spatial memory can be regulated by modulating the activity of hippocampal pyramidal cells via extrasynaptic alpha(5)GABA(A) receptors. In addition, neurons expressing alpha(3)GABA(A) receptors are instrumental in the processing of sensory motor information related to a schizophrenia endophenotype. Finally, during the postnatal development of the brain, the maturation of GABAergic interneurons seems to provide the trigger for the experience-dependent plasticity of neurons in the visual cortex, with alpha(1)GABA(A) receptors setting the time of onset of a critical period of plasticity. Thus, particular neuronal networks defined by respective GABA(A) receptor subtypes can now be linked to the regulation of various clearly defined behavioural patterns. These achievements are of obvious relevance for the pharmacotherapy of certain brain disorders, in particular sleep dysfunctions, anxiety disorders, schizophrenia and diseases associated with memory deficits.
...
PMID:GABA(A) receptor diversity and pharmacology. 1693 11

<< Previous 1 2 3 4 5 6 7 8 Next >>