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GABA Transporter-1 (GAT1)-Deficient Mice: Differential Tonic Activation of GABA_A Versus GABA_B Receptors in the Hippocampus

Jensen, Kimmo and Chiu, Chi-Sung and Sokolova, Irina and Lester, Henry A. and Mody, Istvan (2003) GABA Transporter-1 (GAT1)-Deficient Mice: Differential Tonic Activation of GABA_A Versus GABA_B Receptors in the Hippocampus. Journal of Neurophysiology, 90 (4). pp. 2690-2701. ISSN 0022-3077. doi:10.1152/jn.00240.2003.

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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 GABA_A 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 GABA_A receptors, GABA_B receptors, glutamic acid decarboxylase 65 kDa, and vesicular GAT were unaltered. The GAT1-deficient mice lacked a presynaptic GABA_B 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 GABA_A receptors responsible for a postsynaptic tonic conductance. Chronically elevated GABA levels also downregulate phasic GABA release and reduce presynaptic signaling via GABA_B receptors thus causing an enhanced tonic and a diminished phasic inhibition.

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Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2003 by the American Physiological Society. Submitted 13 March 2003; accepted in final form 9 June 2003. This work was supported by National Institutes of Health Grants DA-09121, DA-010509, NS-11756, MH-49176, MH-61468, NS-30549, DA-14947, National Science Foundation Grant 0119493, and a Della Martin Fellowship to C.-S. Chiu. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. K. Jensen and C.-S. Chiu contributed equally to this work.
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Della Martin FoundationUNSPECIFIED
Issue or Number:4
Record Number:CaltechAUTHORS:20200428-095147178
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Official Citation:GABA Transporter-1 (GAT1)-Deficient Mice: Differential Tonic Activation of GABAA Versus GABAB Receptors in the Hippocampus Kimmo Jensen, Chi-Sung Chiu, Irina Sokolova, Henry A. Lester, and Istvan Mody Journal of Neurophysiology 2003 90:4, 2690-2701
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:102868
Deposited By: George Porter
Deposited On:28 Apr 2020 17:20
Last Modified:16 Nov 2021 18:16

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