Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the primate cerebral cortex, morphologically and functionally diverse classes of local circuit neurons containing the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) differentially regulate the activity of pyramidal cells, the principal type of excitatory output neurons. In schizophrenia, GABA neurotransmission in the prefrontal cortex (PFC) appears to be disturbed but whether specific populations of GABA neurons are affected is not known. The chandelier class of GABA neurons are of particular interest because their axon terminals, which form distinctive arrays termed "cartridges," provide inhibitory input exclusively to the axon initial segment of pyramidal cells. Thus, chandelier cells are positioned to powerfully regulate the excitatory output of pyramidal neurons and, consequently, to substantially affect the patterns of neuronal activity within the PFC. In this study, an antibody directed against the GABA membrane transporter GAT-1 was used to label GABA axon terminals in postmortem human brains. The relative density of GAT-1-immunoreactive axon cartridges furnished by chandelier neurons was decreased by 40% in the PFC of schizophrenic subjects compared with matched groups of normal control and nonschizophrenic psychiatric subjects. In contrast, markers of the axon terminals of other populations of GABA neurons were not altered in the schizophrenic subjects. Furthermore, the density of GAT-1-immunoreactive axon cartridges was not altered in psychiatric subjects who had been treated with antipsychotic medications. The changes in GAT-1-immunoreactive axon cartridges of chandelier neurons in schizophrenia are likely to reflect altered information processing within the PFC and in its output connections to other brain regions and could contribute to the cognitive impairments seen in this disorder.
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PMID:A subclass of prefrontal gamma-aminobutyric acid axon terminals are selectively altered in schizophrenia. 956 Feb 77

The hypothesis that the pathophysiology of schizophrenia may be associated with a dysfunction in GABA transmission in the human prefrontal cortex was investigated. Human post mortem brain tissue from 10 control cases and six cases of schizophrenia were processed for amino acid analysis and for radioactive in situ hybridization. Laminae III and V of three prefrontal cortical areas were examined in detail, namely Brodmann areas 9, 10 and 11. Of these three areas significant changes in GABAergic markers were found only in areas 9 and 10. Of note, a significant decrease in the tissue content of GABA was observed and this was accompanied by a marked increase in the cellular expression of the GABA(A) receptor alpha-1 subunit messenger RNA and a marked decrease in the expression of human GABA transporter-1, the messenger RNA encoding the neuronal GABA transporter protein. The amino acid analysis data provided in this study coupled with the detailed cellular study of several GABAergic markers in the human prefrontal cortex provide direct evidence in support of a disturbance in GABA transmission in the prefrontal cortex, which may be loosely termed "hypofrontality".
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PMID:Measurement of GABAergic parameters in the prefrontal cortex in schizophrenia: focus on GABA content, GABA(A) receptor alpha-1 subunit messenger RNA and human GABA transporter-1 (HGAT-1) messenger RNA expression. 1046 26

The pathophysiology of schizophrenia involves dysfunction of the dorsolateral prefrontal cortex, and this dysfunction may be related to alterations in GABA neurotransmission. Determining the causes and consequences of altered GABA neurotransmission in schizophrenia requires knowledge of which subpopulations of cortical GABA neurons are affected. The chandelier class of GABA neurons are of interest in this regard because their axon terminals form distinctive vertical arrays (termed 'cartridges') which synapse exclusively with the axon initial segments of pyramidal neurons, the principal class of cortical excitatory neurons. We evaluated the integrity of chandelier neuron cell bodies and axon cartridges in PFC areas 9 and 46 of schizophrenic subjects using immunocytochemical techniques and antibodies against parvalbumin and the GABA membrane transporter GAT-1. Schizophrenic subjects did not differ from matched control subjects in the relative density, laminar distribution or size of parvalbumin-containing neurons. In contrast, the density of GAT-1-immunoreactive chandelier neuron axon cartridges was decreased by 40% in schizophrenic subjects compared to both normal controls and subjects with other psychiatric disorders. The axon terminals of other subclasses of GABA neurons did not appear to be similarly affected. These findings suggest that disturbed GABA neurotransmission in the PFC of schizophrenic subjects may be due to a selective alteration of GAT-1 protein in the axon terminals of chandelier neurons.
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PMID:GABAergic local circuit neurons and prefrontal cortical dysfunction in schizophrenia. 1071 53

Postmortem samples from individuals with schizophrenia (n = 13) and control subjects (n = 10) were investigated for binding of [(3)H]tiagabine to GABA transporter-1 GAT-1. The binding was analyzed in the cingulate cortex and the caudate nucleus. There were no differences in binding affinity between the groups in any of the investigated areas. The maximum number of binding sites (B(max)) was elevated in the schizophrenic cingulate cortex compared to controls (1,264 +/- 96 vs. 860 +/- 123 fmol/mg of protein). The B(max) in the caudate nucleus for schizophrenics (426 +/- 40 fmol/mg of protein) was the same as for controls (495 +/- 69 fmol/mg of protein). The increase in GAT-1 in schizophrenia could be explained by a modulatory upregulation in the cingulate cortex.
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PMID:Increased [(3)H]tiagabine binding to GAT-1 in the cingulate cortex in schizophrenia. 1180 35

A defect in neurotransmission involving gamma-amino butyric acid (GABA) in schizophrenia was first proposed in the early 1970s. Since that time, a considerable effort has been made to find such a defect in components of the GABAergic system. After a brief introduction focusing on historical perspectives, this paper reviews post-mortem and other biological studies examining the following components of the GABAergic system in schizophrenic subjects: the GABA biosynthetic enzyme, glutamate decarboxylase; free GABA; the GABA transporter; the GABAA, GABAB and benzodiazepine receptors; and the catabolic enzyme GABA transaminase. Additionally, post-mortem studies using morphology or calcium-binding protein to identify GABAergic neurons are also reviewed. Substantial evidence argues for a defect in the GABAergic system of the frontal cortex in schizophrenia which is limited to the parvalbumin-class of GABAergic interneurons.
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PMID:The GABAergic system in schizophrenia. 1213 41

In schizophrenia, critical deficits in cognitive functions appear to reflect altered neural processing in the prefrontal cortex (PFC). Given the essential role of inhibitory neurotransmission in mediating these cognitive functions, we sought to determine whether abnormalities in the inhibitory circuitry of the PFC may contribute to the cognitive deficits of schizophrenia. In situ hybridization analyses in postmortem brain tissue from subjects with schizophrenia revealed that a subset of GABA neurons in PFC layers 1-5 do not express detectable levels of the mRNAs encoding glutamate decarboxylase (GAD(67)), a synthesizing enzyme for GABA, or the GABA membrane transporter (GAT-1), which is responsible for the reuptake of GABA into the nerve terminal. Furthermore, the affected GABA neurons appear to include chandelier cells, since decreased expression of GAT-1 mRNA is associated with decreased GAT-1 protein immunoreactivity in chandelier neuron axon terminals. Finally, immunocytochemical studies revealed that decreased GAT-1 immunoreactivity in chandelier neuron axon terminals is associated with an increase in a marker of GABA(A) receptors at the postsynaptic targets of chandelier neuron axons, the axon initial segment (AIS) of pyramidal neurons. These findings suggest that schizophrenia is associated with an up-regulation of GABA(A) receptors at pyramidal neuron AIS in response to deficient GABAergic input from chandelier neurons. Selective disruptions in inhibitory neurotransmission are likely to distort aspects of pyramidal neuron function important for working memory tasks, and thus may contribute to cognitive dysfunction in schizophrenia.
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PMID:Impaired prefrontal inhibition in schizophrenia: relevance for cognitive dysfunction. 1252 90

Gamma-Aminobutyric acid (GABA), the principal inhibitory neurotransmitter of CNS, has been consistently implicated in the pathophysiology of schizophrenia. GABA is synthesized from glutamate by the enzyme glutamic acid decarboxylase (GAD). Two isoforms of GAD have been identified and have been named GAD65 and GAD67 based on their apparent molecular weights. In this study, GAD65 and GAD67 mRNA and protein levels were measured by using real-time RT-PCR and immunoblotting, respectively, in post-mortem brain tissue from the dorsolateral prefrontal cortex (DLPFC) and the occipital cortex of the elderly persons with schizophrenia and matched normal controls. In addition, the mRNA expression of GAT-1, one of the principal transporters of GABA, was also studied in the same subjects. Expression of GAD65 and GAD67 mRNA in the DLPFC and in the occipital cortex was significantly elevated in patients with schizophrenia, whereas the expression of the corresponding proteins and GAT-1 mRNA was unchanged. Although the levels of GAD65 and GAD67 messages were increased in schizophrenia subjects, the proportion of the two GAD isoforms remained constant in controls and schizophrenics. In the human DLPFC, GAD65 mRNA was found to be expressed significantly less than the message for GAD67, approximately 16% of that observed for GAD67. On the contrary, the abundance of GAD65 protein in the DLPFC was about 350% of that observed for GAD67. The results suggest a substantial dysregulation of GAD mRNA expression in schizophrenia and, taken together with the results of protein expression studies, raise the possibility that both cortical and subcortical GABA function may be compromised in the disease.
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PMID:GAD67 and GAD65 mRNA and protein expression in cerebrocortical regions of elderly patients with schizophrenia. 1511 30

This study aimed to investigate the binding affinity of [3H]GABA and [3H]beta-alanine to GABA transporters GAT-1 and GAT-3 in the human dorsolateral prefrontal cortex (Brodmanns' area 9) in schizophrenia. Using post mortem tissue from individuals diagnosed with schizophrenia (n=6) and control subjects (n=6), the density of GAT-1 was established by displacing [3H]GABA with muscimol, and for GAT-3 [3H]beta-alanine was used. Data analysis showed a significant decrease of GAT-1 levels (45%), and a significant increase of GAT-3 density (23%) within the dorsolateral prefrontal cortex of individuals diagnosed with schizophrenia when compared to age- and sex-matched controls. The observed decrease of GAT-1 could be explained as a consequence of the GABA hypo-function or the result of volumetric shrinkage of the cerebral cortex previously reported in this disease. The observed elevation of GAT-3 levels could be due to a compensatory effect for any functional loss of GABA re-uptake by the decreased GAT-1 levels.
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PMID:GABA transporters GAT-1 and GAT-3 in the human dorsolateral prefrontal cortex in schizophrenia. 1536 20

Chandelier neurons and their characteristic arrays of axonal terminals, known as cartridges, have been implicated in a variety of psychiatric and neurological disorders including schizophrenia and epilepsy. As a result, these neurons have been extensively examined in the brains of several species using a range of markers. However, these markers have not been systematically compared in a single species for their robustness in labelling chandelier cell cartridges. We have therefore examined several markers, reported to label chandelier arrays in primates, for their capacity to mark these structures in rat medial prefrontal cortex and hippocampus. These studies revealed that cartridge-like structures were labelled by parvalbumin and GAT-1 immunohistochemistry in both medial prefrontal cortex and hippocampus of the rat brain. Additionally, GAD65 immunohistochemistry labelled array-like structures preferentially in the dentate gyrus. In contrast, PSA-NCAM, calbindin and GAD67 immunohistochemistry did not reveal any array-like structures in either region of rat brain. These observations indicate that the various immunological markers previously used to visualise chandelier cell cartridges in primates are not equally efficient in labelling these structures in the rat brain, and that GAT-1 immunohistochemistry is the most robust means of visualising chandelier cell cartridges in the regions examined. These are important considerations for quantitative studies in animal models of neurological disorders where chandelier neurons are implicated.
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PMID:A comparison of possible markers for chandelier cartridges in rat medial prefrontal cortex and hippocampus. 1564 49

The extracellular region of the transmembrane neural cell adhesion molecule (NCAM-EC) is shed as a soluble fragment at elevated levels in the schizophrenic brain. A novel transgenic mouse line was generated to identify consequences on cortical development and function of expressing soluble NCAM-EC from the neuron-specific enolase promoter in the developing and mature neocortex and hippocampus. NCAM-EC transgenic mice exhibited a striking reduction in synaptic puncta of GABAergic interneurons in the cingulate, frontal association cortex, and amygdala but not hippocampus, as shown by decreased immunolabeling of glutamic acid decarboxylase-65 (GAD65), GAD67, and GABA transporter 1. Interneuron cell density was unaltered in the transgenic mice. Affected subpopulations of interneurons included basket interneurons evident in NCAM-EC transgenic mice intercrossed with a reporter line expressing green fluorescent protein and by parvalbumin staining. In addition, there appeared to be a reduction in excitatory synapses, as revealed by synaptophysin staining and apical dendritic spine density of cortical pyramidal cells. Behavioral analyses demonstrated higher basal locomotor activity of NCAM-EC mice and enhanced responses to amphetamine and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate compared with wild-type controls. Transgenic mice were deficient in prepulse inhibition, which was restored by clozapine but not by haloperidol. Additionally, NCAM-EC mice were impaired in contextual and cued fear conditioning. These results suggested that elevated shedding of NCAM perturbs synaptic connectivity of GABAergic interneurons and produces abnormal behaviors that may be relevant to schizophrenia and other neuropsychiatric disorders.
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PMID:Neural cell adhesion molecule-secreting transgenic mice display abnormalities in GABAergic interneurons and alterations in behavior. 1587 14


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