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J Neurophysiol 90: 2690-2701, 2003. First published June 18, 2003; doi:10.1152/jn.00240.2003
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GABA Transporter-1 (GAT1)-Deficient Mice: Differential Tonic Activation of GABAA Versus GABAB Receptors in the Hippocampus

Kimmo Jensen1,*, Chi-Sung Chiu2,*, Irina Sokolova2, Henry A. Lester2 and Istvan Mody1

1 Departments of Neurology and Physiology, University of California Los Angeles School of Medicine, Los Angeles, California 90095; 2 Division of Biology, California Institute of Technology, Pasadena, California 91125

Submitted 13 March 2003; accepted in final form 9 June 2003

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.

Address for reprint requests and other correspondence: I. Mody, Dept. of Neurology, The David Geffen School of Medicine at UCLA, 710 Westwood Plaza, RNRC 3-155, Los Angeles, CA 90095-1769 (E-mail: mody{at}ucla.edu).




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