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The Journal of Neuroscience, March 22, 2006, 26(12):3357-3364; doi:10.1523/JNEUROSCI.4799-05.2006

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Cellular/Molecular
Contributions of the GABA_A Receptor 6 Subunit to Phasic and Tonic Inhibition Revealed by a Naturally Occurring Polymorphism in the 6 Gene

Vijayalakshmi Santhakumar,¹ H. Jacob Hanchar,² Martin Wallner,² Richard W. Olsen,² and Thomas S. Otis¹

Departments of ¹Neurobiology and ²Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095

Correspondence should be addressed to Dr. Thomas S. Otis, Department of Neurobiology, University of California, Los Angeles, Box 951763, 63-314 Center for Health Sciences, Los Angeles, CA 90095-1763. Email: otist{at}ucla.edu

GABA_A receptors (GABARs) are heteromultimeric proteins composed of five subunits. The specific subunit composition determines critical properties of a GABAR such as pharmacological sensitivities and whether the receptor contributes to synaptic or extrasynaptic forms of inhibition. Classically, synaptic but not extrasynaptic GABARs are thought to respond to benzodiazepines, whereas the reverse has been suggested for ethanol. To examine the effects of subunit composition on GABAR function in situ, we took advantage of two naturally occurring alleles of the rat gene for GABAR subunit 6 (Gabra6^100R and Gabra6^100Q). Depending on their subunit partners, these two variants of 6 can lead to differential sensitivities to benzodiazepines and ethanol. An examination of synaptic and extrasynaptic GABA-mediated currents in cerebellar granule cells from Gabra6^100R/100R and Gabra6^100Q/100Q rats uncovered marked allele-dependent differences in benzodiazepine sensitivity. Unexpectedly, we found that the benzodiazepines flunitrazepam and diazepam enhanced extrasynaptic inhibition mediated by subunit-containing GABARs in Gabra6^100Q/100Q rats. Complementary experiments on recombinant GABARs confirmed that, at subsaturating [GABA], flunitrazepam potentiates 6/ subunit-containing GABARs. Based on data and a simple theoretical analysis, we estimate that the average extrasynaptic [GABA] is 160 nM in perfused slices. These results (1) demonstrate contributions of 6 subunits to both synaptic and extrasynaptic GABA responses, (2) establish that subunit-containing GABARs are benzodiazepine sensitive at subsaturating [GABA] and, (3) provide an empirical estimate of extrasynaptic [GABA] in slices.

Key words: granule cell; cerebellum; benzodiazepine; flunitrazepam; flumazenil; extrasynaptic inhibition

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Received July 10, 2005; revised Feb. 6, 2006; accepted Feb. 7, 2006.

Correspondence should be addressed to Dr. Thomas S. Otis, Department of Neurobiology, University of California, Los Angeles, Box 951763, 63-314 Center for Health Sciences, Los Angeles, CA 90095-1763. Email: otist{at}ucla.edu

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