Prolonged Exposure to NMDAR Antagonist Suppresses Inhibitory Synaptic Transmission in Prefrontal Cortex

Postmortem studies have shown that schizophrenia produces a reduction in the 67-kilodalton isoform of glutamic acid decarboxylase (GAD67), a key enzyme for γ-aminobutyric acid (GABA) synthesis. N-methyl-d-aspartate receptor (NMDAR) antagonists have been extensively used to study schizophrenia becaus...

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Main Authors: Zhang, Yuchun, Behrens, M. Margarita, Lisman, John E.
Formato: Artigo
Idioma:English
Publicado em: American Physiological Society 2008
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Acesso em linha:https://ncbi.nlm.nih.gov/pmc/articles/PMC2525704/
https://ncbi.nlm.nih.gov/pubmed/18525022
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1152/jn.00079.2008
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spelling pubmed-25257042009-08-01 Prolonged Exposure to NMDAR Antagonist Suppresses Inhibitory Synaptic Transmission in Prefrontal Cortex Zhang, Yuchun Behrens, M. Margarita Lisman, John E. J Neurophysiol Articles Postmortem studies have shown that schizophrenia produces a reduction in the 67-kilodalton isoform of glutamic acid decarboxylase (GAD67), a key enzyme for γ-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. American Physiological Society 2008-08 2008-06-04 /pmc/articles/PMC2525704/ /pubmed/18525022 http://dx.doi.org/10.1152/jn.00079.2008 Text en Copyright © 2008, American Physiological Society
institution US National Library of Medicine
collection PubMed Central
language English
format Article
topic Articles
spellingShingle Articles
Zhang, Yuchun
Behrens, M. Margarita
Lisman, John E.
Prolonged Exposure to NMDAR Antagonist Suppresses Inhibitory Synaptic Transmission in Prefrontal Cortex
description Postmortem studies have shown that schizophrenia produces a reduction in the 67-kilodalton isoform of glutamic acid decarboxylase (GAD67), a key enzyme for γ-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.
author Zhang, Yuchun
Behrens, M. Margarita
Lisman, John E.
author_facet Zhang, Yuchun
Behrens, M. Margarita
Lisman, John E.
author_sort Zhang, Yuchun
title Prolonged Exposure to NMDAR Antagonist Suppresses Inhibitory Synaptic Transmission in Prefrontal Cortex
title_short Prolonged Exposure to NMDAR Antagonist Suppresses Inhibitory Synaptic Transmission in Prefrontal Cortex
title_full Prolonged Exposure to NMDAR Antagonist Suppresses Inhibitory Synaptic Transmission in Prefrontal Cortex
title_fullStr Prolonged Exposure to NMDAR Antagonist Suppresses Inhibitory Synaptic Transmission in Prefrontal Cortex
title_full_unstemmed Prolonged Exposure to NMDAR Antagonist Suppresses Inhibitory Synaptic Transmission in Prefrontal Cortex
title_sort prolonged exposure to nmdar antagonist suppresses inhibitory synaptic transmission in prefrontal cortex
publisher American Physiological Society
publisher_facet American Physiological Society
publishDate 2008
url https://ncbi.nlm.nih.gov/pmc/articles/PMC2525704/
https://ncbi.nlm.nih.gov/pubmed/18525022
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1152/jn.00079.2008
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