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)

Knowledge concerning the classification of mental disorders progressed substantially with the use of DSM III-IV and IDCD 10 because it was based on observed data, with precise definitions. These classifications a priori avoided to generate definitions related to etiology or treatment response. They are based on a categorical approach where diagnostic entities share common phenomenological features. Modifications proposed or discussed are related to the weak validity of the classification strategy described above. (a) Disorders are supposed to be independent but the current coexistence of two or more disorders is the rule; (b) They also are supposed to have stability, however anxiety disorders most of the time precede major depression. For GAD age at onset, family history, biology and symptomatology are close to those of depression. As a consequence broader entities such as depression-GAD spectrum, panic-phobias spectrum and OCD spectrum including eating disorders and pathological gambling are taken into consideration; (c) Diagnostic categories use thresholds to delimitate a border with normals. This creates "subthreshold" conditions. The relevance of such conditions is well documented. Measuring the presence and severity of different dimensions, independent from a threshold, will improve the relevance of the description of patients pathology. In addition, this dimensional approach will improve the problems posed by the mutually exclusive diagnoses (depression and GAD, schizophrenia and depression); (d) Some disorders are based on the coexistence of different dimensions. Patients may present only one set of symptoms and have different characteristics, evolution and response to treatment. An example would be negative symptoms in Schizophrenia; (e) Because no etiological model is available and most measures are subjective, objective measures (cognitive, biological) and genetics progresses created important hopes. None of these measures is pathognomonic and most appear to be related to risk factors especially at certain periods when associated with environmental events. One of the major aims for a classification of patients is to identify groups to whom a best possible therapeutic strategy can be proposed. Drugs may improve fear extinction while the genetic and/or acquired avoidance may be called phobia. The basic mechanism and or the corresponding phenotype should appear in the classification. Progresses in early identification of disturbances by taking into account all the information available (prodromal symptoms, cognitive, biological, imaging, genetic, family information) are crucial for the future therapeutic strategy: prevention.
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PMID:Refinement of diagnosis and disease classification in psychiatry. 1834 44

Postmortem studies have shown that schizophrenia produces a reduction in the 67-kilodalton isoform of glutamic acid decarboxylase (GAD67), a key enzyme for gamma-aminobutyric acid (GABA) synthesis. N-methyl-d-aspartate receptor (NMDAR) antagonists have been extensively used to study schizophrenia because they can induce many aspects of the disease, including the decrease in GAD67. It is generally thought that this reduction in GAD implies a reduction in functional inhibition, but direct evidence had been lacking. We have therefore performed physiological studies in slices of prefrontal cortex taken from rats treated with the NMDAR antagonist ketamine. Both frequency and amplitude of miniature inhibitory postsynaptic currents were reduced. Consistent with a reduction of inhibition, we observed an increase in postsynaptic excitability. The increased excitability is likely to result from disinhibition because miniature excitatory postsynaptic current properties and intrinsic excitability were not changed. Ketamine did not affect inhibition or GAD levels in young rats, indicating a developmental regulation that may be related to the developmental increase in ketamine sensitivity that occurs in humans. Our results show that NMDAR antagonist produces biochemical changes in the GABA system that lead to a functional disinhibition. Such disinhibition would be expected to decrease gamma oscillations, which are reduced in schizophrenia.
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PMID:Prolonged exposure to NMDAR antagonist suppresses inhibitory synaptic transmission in prefrontal cortex. 1852 22

Tobacco smoking is frequently abused by schizophrenia patients (SZP). The major synaptically active component inhaled from cigarettes is nicotine, hence the smoking habit of SZP may represent an attempt to use nicotine self-medication to correct (i) a central nervous system nicotinic acetylcholine receptor (nAChR) dysfunction, (ii) DNA-methyltransferase 1 (DMT1) overexpression in GABAergic neurons, and (iii) the down-regulation of reelin and GAD(67) expression caused by the increase of DNMT1-mediated hypermethylation of promoters in GABAergic interneurons of the telencephalon. Nicotine (4.5-22 micromol/kg s.c., 4 injections during the 12-h light cycle for 4 days) decreases DNMT1 mRNA and protein and increases GAD(67) expression in the mouse frontal cortex (FC). This nicotine-induced decrease of DNMT1 mRNA expression is greater (80%) in laser microdissected FC layer I GABAergic neurons than in the whole FC (40%), suggesting selectivity differences for the specific nicotinic receptor populations expressed in GABAergic neurons of different cortical layers. The down-regulation of DNMT1 expression induced by nicotine in the FC is also observed in the hippocampus but not in striatal GABAergic neurons. Furthermore, these data show that in the FC, the same doses of nicotine that decrease DNMT1 expression also (i) diminished the level of cytosine-5-methylation in the GAD(67) promoter and (ii) prevented the methionine-induced hypermethylation of the same promoter. Pretreatment with mecamylamine (6 micromol/kg s.c.), an nAChR blocker that penetrates the blood-brain barrier, prevents the nicotine-induced decrease of FC DNMT1 expression. Taken together, these results suggest that nicotine, by activating nAChRs located on cortical or hippocampal GABAergic interneurons, can up-regulate GAD(67) expression via an epigenetic mechanism. Nicotine is not effective in striatal medium spiny GABAergic neurons that primarily express muscarinic receptors.
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PMID:Nicotine decreases DNA methyltransferase 1 expression and glutamic acid decarboxylase 67 promoter methylation in GABAergic interneurons. 1885 56

Animals with a neonatal ventral hippocampal lesion (NVHL) develop abnormal behaviors during or after adolescence, suggesting that early insults can have delayed consequences. Many of these behaviors depend on the prefrontal cortex (PFC), and we have reported that PFC pyramidal neurons of adult rats with an NVHL respond to stimulation of the ventral tegmental area with an increase in firing instead of the characteristic decrease. As the dopamine modulation of cortical interneurons matures during adolescence, these findings raise the possibility that maturation of local inhibitory circuits within the PFC may have been altered in NVHL rats. Here, we assessed the state of PFC interneurons in NVHL rats with in situ hybridization measures of the mRNAs for the calcium binding protein parvalbumin (PV) and the GABA synthesizing enzyme GAD(67), as well as with electrophysiological measures of interneuron function. Although no differences were observed with PV or GAD(67), whole-cell recordings in slices revealed abnormal responses to the D(2) agonist quinpirole in interneurons from NVHL rats. The loss of D(2) modulation of local inhibition in slices from NVHL rats was also evident in the absence of a lasting component in the D(2) attenuation of excitatory synaptic responses in pyramidal neurons, which in sham treated rats was picrotoxin sensitive. The results suggest that the neonatal lesion causes improper maturation, but not loss, of PFC interneurons during adolescence, a finding consistent with current interpretations of imaging data in schizophrenia that suggest a hyperactive, "noisy" cortex underlying dysfunction in the PFC and other cortical areas.
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PMID:A neonatal ventral hippocampal lesion causes functional deficits in adult prefrontal cortical interneurons. 1903 62

Recent advances in schizophrenia (SZ) research indicate that the telencephalic gamma-aminobutyric acid (GABA)ergic neurotransmission deficit associated with this psychiatric disorder probably is mediated by the hypermethylation of the glutamic acid decarboxylase 67 (GAD(67)), reelin and other GABAergic promoters. A pharmacological strategy to reduce the hypermethylation of GABAergic promoters is to induce a DNA-cytosine demethylation by altering the chromatin remodeling with valproate (VPA). When co-administered with VPA, the clinical efficacy of atypical antipsychotics is enhanced. This prompted us to investigate whether this increase in drug efficacy is related to a modification of GABAergic-promoter methylation via chromatin remodeling. Our previous and present results strongly indicate that VPA facilitates chromatin remodeling when it is associated with clozapine or sulpiride but not with haloperidol or olanzapine. This remodeling might contribute to reelin- and GAD(67)-promoter demethylation and might reverse the GABAergic-gene-expression downregulation associated with SZ morbidity.
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PMID:Characterization of the action of antipsychotic subtypes on valproate-induced chromatin remodeling. 1911 Mar 20

Reduced levels of glutamic acid decarboxylase(67) (GAD(67)), an essential enzyme for GABA synthesis, is one of the most consistent gene expression changes found in the frontal cortex of patients with schizophrenia. Recently this reduction has been shown to extend to other areas including primary sensory, primary motor and anterior cingulate (ACC) cortices. To determine the extent to which additional cortical and subcortical regions may be affected in schizophrenia, we measured the level of GAD(67) mRNA in previously unexplored areas including the orbitofrontal (OFC) and superior temporal (STG) cortices as well as the caudate, putamen, nucleus accumbens, medial dorsal thalamus and anterior thalamus using in situ hybridization. We also examined GAD(67) mRNA levels in all these regions in individuals with bipolar disorder and major depression. ANCOVA comparing GAD(67) mRNA levels in all four diagnostic groups revealed a significant reduction (approximately 30%) in layers III and IV of the OFC of patients with schizophrenia and bipolar disorder. A priori t-tests comparing GAD(67) mRNA levels between the schizophrenia and control groups revealed significant reductions in the ACC, STG, striatum and thalamus. These findings suggest that there may be a widespread reduction in GABA neurotransmission due to a decrease in the synthesis of GAD(67) in subjects with psychiatric disorders. The resulting decrease in inhibitory tone across multiple brain areas may contribute to the psychotic behavior observed in patients with schizophrenia and bipolar disorder.
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PMID:Decreased glutamic acid decarboxylase(67) mRNA expression in multiple brain areas of patients with schizophrenia and mood disorders. 1932 Nov 77

GABA cell dysfunction in both schizophrenia (SZ) and bipolar disorder (BD) involves decreased GAD(67) expression, although this change involves fundamentally different networks of genes in the 2 disorders. One gene that is common to these 2 networks is cyclin D2, a key component of cell cycle regulation that shows increased expression in SZ, but decreased expression in BD. Because of the importance of cell cycle regulation in maintaining functional differentiation and DNA repair, the current study has examined the genes involved in the G(1) and G(2) checkpoints to generate new hypotheses regarding the regulation of the GABA cell phenotype in the hippocampus of SZ and BD. The results have demonstrated significant changes in cell cycle regulation in both SZ and BD and these changes include the transcriptional complex (TC) that controls the expression of E2F/DP-1 target genes critical for progression to G(2)/M. The methyl-CpG binding domain protein (MBD4) that is pivotal for DNA repair, is significantly up-regulated in the stratum oriens (SO) of CA3/2 and CA1 in SZs and BDs. However, other genes associated with the TC, and the G(1) and G(2) checkpoints, show complex changes in expression in the SO of CA3/2 and CA1 of both SZs and BDS. Overall, the patterns of expression observed have suggested that the regulation of functional differentiation and/or genomic integrity of hippocampal GABA cells varies according to diagnosis and their location within the trisynaptic pathway.
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PMID:Site-specific regulation of cell cycle and DNA repair in post-mitotic GABA cells in schizophrenic versus bipolars. 1956 23

One of the most consistent findings in schizophrenia is the decreased expression of the GABA synthesizing enzymes GAD(67) and GAD(65) in specific interneuron populations. This dysfunction is observed in distributed brain regions including the prefrontal cortex, hippocampus, and cerebellum. In an effort to understand the mechanisms for this GABA deficit, we investigated the effect of the N-methyl-D-aspartate receptor (NMDAR) antagonist phencyclidine (PCP), which elicits schizophrenia-like symptoms in both humans and animal models, in a chronic, low-dose exposure paradigm. Adult rats were given PCP at a dose of 2.58 mg/kg/day i.p. for a month, after which levels of various GABAergic cell mRNAs and other neuromodulators were examined in the cerebellum by qRT-PCR. Administration of PCP decreased the expression of GAD(67), GAD(65), and the presynaptic GABA transporter GAT-1, and increased GABA(A) receptor subunits similar to those seen in patients with schizophrenia. Additionally, we found that the mRNA levels of two Golgi cell selective NMDAR subunits, NR2B and NR2D, were decreased in PCP-treated rats. Furthermore, we localized the deficits in GAD(67) expression solely to these interneurons. Slice electrophysiological studies showed that spontaneous firing of Golgi cells was reduced by acute exposure to low-dose PCP, suggesting that these neurons are particularly vulnerable to NMDA receptor antagonism. In conclusion, our results demonstrate that chronic exposure to low levels of PCP in rats mimics the GABAergic alterations reported in the cerebellum of patients with schizophrenia (Bullock et al., 2008. Am. J. Psychiatry 165, 1594-1603), further supporting the validity of this animal model.
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PMID:Schizophrenia-like GABAergic gene expression deficits in cerebellar Golgi cells from rats chronically exposed to low-dose phencyclidine. 1965 Nov 69

D2 and D4 dopamine receptors play an important role in cognitive functions in the prefrontal cortex and they are involved in the pathophysiology of neuropsychiatric disorders such as schizophrenia. The eventual effect of dopamine upon pyramidal neurons in the prefrontal cortex depends on which receptors are expressed in the different neuronal populations. Parvalbumin and calbindin mark two subpopulations of cortical GABAergic interneurons that differently innervate pyramidal cells. Recent hypotheses about schizophrenia hold that the root of the illness is a dysfunction of parvalbumin chandelier cells that produces disinhibition of pyramidal cells. In the present work we report double in situ hybridization histochemistry experiments to determine the prevalence of D2 receptor mRNA and D4 receptor mRNA in glutamatergic neurons, GABAergic interneurons and both parvalbumin and calbindin GABAergic subpopulations in monkey prefrontal cortex layer V. We found that around 54% of glutamatergic neurons express D2 mRNA and 75% express D4 mRNA, while GAD-positive interneurons express around 34% and 47% respectively. Parvalbumin cells mainly expressed D4 mRNA (65%) and less D2 mRNA (15-20%). Finally, calbindin cells expressed both receptors in similar proportions (37%). We hypothesized that D4 receptor could be a complementary target in designing new antipsychotics, mainly because of its predominance in parvalbumin interneurons.
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PMID:D2 and D4 dopamine receptor mRNA distribution in pyramidal neurons and GABAergic subpopulations in monkey prefrontal cortex: implications for schizophrenia treatment. 2072 49

Nonselective benzodiazepines exert their pharmacological effects via GABAA receptors containing either an alpha1, alpha2, alpha3, or alpha5 subunit. The use of subtype-selective tool compounds along with transgenic mice has formed the conceptual framework for defining the requirements of subtype-selective compounds with potentially novel pharmacological profiles. More specifically, compounds which allosterically modulate the alpha2 and/or alpha3 subtypes but are devoid of, or have much reduced, effects at the alpha1 subtype are hypothesized to be anxioselective (i.e., anxiolytic but devoid of sedation). Accordingly, three compounds, MRK-409, TPA023 and TPA023B, which selectively potentiated the effects of GABA at the alpha2 and alpha3 compared to alpha1 subtypes were progressed into man. All three compounds behaved as nonsedating anxiolytics in preclinical (rodent and primate) species but, surprisingly, MRK-409 produced sedation in man at relatively low levels of occupancy (< 10%). This sedation liability of MRK-409 in man was attributed to its weak partial agonist efficacy at the alpha1 subtype since both TPA023 and TPA023B lacked any alpha1 efficacy and did not produce overt sedation even at relatively high levels of occupancy (> 50%). The anxiolytic efficacy of TPA023 was evaluated in Generalized Anxiety Disorder and although these clinical trials were terminated early due to preclinical toxicity issues, the combined data from these incomplete studies demonstrated an anxiolytic-like effect of TPA023. This compound also showed a trend to increase cognitive performance in a small group of schizophrenic subjects and is currently under further evaluation of its cognition-enhancing effects in schizophrenia as part of the TURNS initiative. In contrast, the fate of the back-up clinical candidate TPA023B has not been publicly disclosed. At the very least, these data indicate that the pharmacological profile of compounds that differentially modulate specific populations of GABAA receptors is distinct from classical benzodiazepines and should encourage further preclinical and clinical investigation of such compounds, with the caveat that, as exemplified by MRK-409, the preclinical profile might not necessarily translate into man.
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PMID:GABAA receptor alpha2/alpha3 subtype-selective modulators as potential nonsedating anxiolytics. 2130 16

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