HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 101/3/1179    most recent 91203.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Zarnowska, E. D. Articles by Pearce, R. A. Search for Related Content PubMed PubMed Citation Articles by Zarnowska, E. D. Articles by Pearce, R. A.

GABA_A Receptor 5 Subunits Contribute to GABA_A,slow Synaptic Inhibition in Mouse Hippocampus

¹Department of Anesthesiology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin; ²Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland; and ³Laboratory of Genetic Neuropharmacology, McLean Hospital, Department of Psychiatry, Harvard Medical School, Belmont, Massachusetts

Submitted 10 November 2008; accepted in final form 5 December 2008

Abstract

-Aminobutyric acid type A (GABA_A) receptor 5 subunits, which are heavily expressed in the hippocampus, are potential drug targets for improving cognitive function. They are found at synaptic and extrasynaptic sites and have been shown to mediate tonic inhibition in pyramidal neurons. We tested the hypothesis that 5 subunits also contribute to synaptic inhibition by measuring the effect of diazepam (DZ) on spontaneous and stimulus-evoked inhibitory postsynaptic currents (IPSCs) in genetically modified mice carrying a point mutation in the 5 subunit (5-H105R) that renders those receptors insensitive to benzodiazepines. In wild type mice, DZ (1 µM) increased the amplitude of spontaneous IPSCs (sIPSCs) and stimulus-evoked GABA_A,slow IPSCs (eIPSCs) and prolonged the decay of GABA_A,fast sIPSCs. In 5-mutant mice, DZ increased the amplitude of a small-amplitude subset of sIPSCs (<50 pA) and eIPSCs (<300 pA) GABA_A,slow and prolonged the decay of GABA_A,fast sIPSCs, but failed to increase the amplitude of larger sIPSCs and eIPSCs GABA_A,slow. These results indicate that 5 subunits contribute to a large-amplitude subset of GABA_A,slow synapses and implicate these synapses in modulation of cognitive function by drugs that target 5 subunits.