Document Detail


GABA transporter-1 (GAT1)-deficient mice: differential tonic activation of GABAA versus GABAB receptors in the hippocampus.
MedLine Citation:
PMID:  12815026     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
After its release from interneurons in the CNS, the major inhibitory neurotransmitter GABA is taken up by GABA transporters (GATs). The predominant neuronal GABA transporter GAT1 is localized in GABAergic axons and nerve terminals, where it is thought to influence GABAergic synaptic transmission, but the details of this regulation are unclear. To address this issue, we have generated a strain of GAT1-deficient mice. We observed a large increase in a tonic postsynaptic hippocampal GABAA receptor-mediated conductance. There was little or no change in the waveform or amplitude of spontaneous inhibitory postsynaptic currents (IPSCs) or miniature IPSCs. In contrast, the frequency of quantal GABA release was one-third of wild type (WT), although the densities of GABAA receptors, GABAB receptors, glutamic acid decarboxylase 65 kDa, and vesicular GAT were unaltered. The GAT1-deficient mice lacked a presynaptic GABAB receptor tone, present in WT mice, which reduces the frequency of spontaneous IPSCs. We conclude that GAT1 deficiency leads to enhanced extracellular GABA levels resulting in an overactivation of GABAA receptors responsible for a postsynaptic tonic conductance. Chronically elevated GABA levels also downregulate phasic GABA release and reduce presynaptic signaling via GABAB receptors thus causing an enhanced tonic and a diminished phasic inhibition.
Authors:
Kimmo Jensen; Chi-Sung Chiu; Irina Sokolova; Henry A Lester; Istvan Mody
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Publication Detail:
Type:  Comparative Study; In Vitro; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.     Date:  2003-06-18
Journal Detail:
Title:  Journal of neurophysiology     Volume:  90     ISSN:  0022-3077     ISO Abbreviation:  J. Neurophysiol.     Publication Date:  2003 Oct 
Date Detail:
Created Date:  2003-10-09     Completed Date:  2004-01-05     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0375404     Medline TA:  J Neurophysiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2690-701     Citation Subset:  IM    
Affiliation:
Department of Neurology, University of California Los Angeles School of Medicine, Los Angeles, California 90095, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Carrier Proteins / genetics
GABA Plasma Membrane Transport Proteins
Hippocampus / metabolism*
Membrane Proteins / deficiency*,  genetics
Membrane Transport Proteins*
Mice
Mice, Inbred C57BL
Mice, Knockout
Organic Anion Transporters*
Receptors, GABA-A / genetics,  metabolism*
Receptors, GABA-B / genetics,  metabolism*
Synaptic Transmission / physiology*
Grant Support
ID/Acronym/Agency:
DA-010509/DA/NIDA NIH HHS; DA-09121/DA/NIDA NIH HHS; DA-14947/DA/NIDA NIH HHS; MH-49176/MH/NIMH NIH HHS; MH-61468/MH/NIMH NIH HHS; NS-11756/NS/NINDS NIH HHS; NS-30549/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Carrier Proteins; 0/GABA Plasma Membrane Transport Proteins; 0/Membrane Proteins; 0/Membrane Transport Proteins; 0/Organic Anion Transporters; 0/Receptors, GABA-A; 0/Receptors, GABA-B; 0/Slc6a1 protein, mouse

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