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Dysfunctional GABAergic inhibition in the prefrontal cortex leading to "psychotic" hyperactivation

BACKGROUND: The GABAergic system in the brain seems to be dysfunctional in various psychiatric disorders. Many studies have suggested so far that, in schizophrenia patients, GABAergic inhibition is selectively but consistently reduced in the prefrontal cortex (PFC). RESULTS: This study used a comput...

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Autor principal: Tanaka, Shoji
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2387163/
https://www.ncbi.nlm.nih.gov/pubmed/18439259
http://dx.doi.org/10.1186/1471-2202-9-41
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author Tanaka, Shoji
author_facet Tanaka, Shoji
author_sort Tanaka, Shoji
collection PubMed
description BACKGROUND: The GABAergic system in the brain seems to be dysfunctional in various psychiatric disorders. Many studies have suggested so far that, in schizophrenia patients, GABAergic inhibition is selectively but consistently reduced in the prefrontal cortex (PFC). RESULTS: This study used a computational model of the PFC to investigate the dynamics of the PFC circuit with and without chandelier cells and other GABAergic interneurons. The inhibition by GABAergic interneurons other than chandelier cells effectively regulated the PFC activity with rather low or modest levels of dopaminergic neurotransmission. This activity of the PFC is associated with normal cognitive functions and has an inverted-U shaped profile of dopaminergic modulation. In contrast, the chandelier cell-type inhibition affected only the PFC circuit dynamics in hyperdopaminergic conditions. Reduction of chandelier cell-type inhibition resulted in bistable dynamics of the PFC circuit, in which the upper stable state is associated with a hyperactive mode. When both types of inhibition were reduced, this hyperactive mode and the conventional inverted-U mode merged. CONCLUSION: The results of our simulation suggest that, in schizophrenia, a reduction of GABAergic inhibition increases vulnerability to psychosis by (i) producing the hyperactive mode of the PFC with hyperdopaminergic neurotransmission by dysfunctional chandelier cells and (ii) increasing the probability of the transition to the hyperactive mode from the conventional inverted-U mode by dysfunctional GABAergic interneurons.
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spelling pubmed-23871632008-05-20 Dysfunctional GABAergic inhibition in the prefrontal cortex leading to "psychotic" hyperactivation Tanaka, Shoji BMC Neurosci Research Article BACKGROUND: The GABAergic system in the brain seems to be dysfunctional in various psychiatric disorders. Many studies have suggested so far that, in schizophrenia patients, GABAergic inhibition is selectively but consistently reduced in the prefrontal cortex (PFC). RESULTS: This study used a computational model of the PFC to investigate the dynamics of the PFC circuit with and without chandelier cells and other GABAergic interneurons. The inhibition by GABAergic interneurons other than chandelier cells effectively regulated the PFC activity with rather low or modest levels of dopaminergic neurotransmission. This activity of the PFC is associated with normal cognitive functions and has an inverted-U shaped profile of dopaminergic modulation. In contrast, the chandelier cell-type inhibition affected only the PFC circuit dynamics in hyperdopaminergic conditions. Reduction of chandelier cell-type inhibition resulted in bistable dynamics of the PFC circuit, in which the upper stable state is associated with a hyperactive mode. When both types of inhibition were reduced, this hyperactive mode and the conventional inverted-U mode merged. CONCLUSION: The results of our simulation suggest that, in schizophrenia, a reduction of GABAergic inhibition increases vulnerability to psychosis by (i) producing the hyperactive mode of the PFC with hyperdopaminergic neurotransmission by dysfunctional chandelier cells and (ii) increasing the probability of the transition to the hyperactive mode from the conventional inverted-U mode by dysfunctional GABAergic interneurons. BioMed Central 2008-04-25 /pmc/articles/PMC2387163/ /pubmed/18439259 http://dx.doi.org/10.1186/1471-2202-9-41 Text en Copyright © 2008 Tanaka; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Tanaka, Shoji
Dysfunctional GABAergic inhibition in the prefrontal cortex leading to "psychotic" hyperactivation
title Dysfunctional GABAergic inhibition in the prefrontal cortex leading to "psychotic" hyperactivation
title_full Dysfunctional GABAergic inhibition in the prefrontal cortex leading to "psychotic" hyperactivation
title_fullStr Dysfunctional GABAergic inhibition in the prefrontal cortex leading to "psychotic" hyperactivation
title_full_unstemmed Dysfunctional GABAergic inhibition in the prefrontal cortex leading to "psychotic" hyperactivation
title_short Dysfunctional GABAergic inhibition in the prefrontal cortex leading to "psychotic" hyperactivation
title_sort dysfunctional gabaergic inhibition in the prefrontal cortex leading to "psychotic" hyperactivation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2387163/
https://www.ncbi.nlm.nih.gov/pubmed/18439259
http://dx.doi.org/10.1186/1471-2202-9-41
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