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The Journal of Neuroscience, June 15, 1999, 19(12):4921-4937

GABA_A Receptor Subunit Composition and Functional Properties of Cl Channels with Differential Sensitivity to Zolpidem in Embryonic Rat Hippocampal Cells

Dragan Maric¹, Irina Maric¹, Xiling Wen¹, Jean-Marc Fritschy², Werner Sieghart³, Jeffery L. Barker¹, and Ruggero Serafini¹

¹ Laboratory of Neurophysiology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, ² Institute of Pharmacology, University of Zurich, CH-8057 Zurich, Switzerland, and ³ Department of Biochemical Psychiatry, University Clinic for Psychiatry, A-1090 Vienna, Austria

Using flow cytometry in conjunction with a voltage-sensitive fluorescent indicator dye (oxonol), we have identified and separated embryonic hippocampal cells according to the sensitivity of their functionally expressed GABA_A receptors to zolpidem. Immunocytochemical and RT-PCR analysis of sorted zolpidem-sensitive (ZS) and zolpidem-insensitive (ZI) subpopulations identified ZS cells as postmitotic, differentiating neurons expressing 2, 4, 5, 1, 2, 3, 1, 2, and 3 GABA_A receptor subunits, whereas the ZI cells were neuroepithelial cells or newly postmitotic neurons, expressing predominantly 4, 5, 1, and 2 subunits. Fluctuation analyses of macroscopic Cl currents evoked by GABA revealed three kinetic components of GABA_A receptor/Cl channel activity in both subpopulations. We focused our study on ZI cells, which exhibited a limited number of subunits and functional channels, to directly correlate subunit composition with channel properties. Biophysical analyses of GABA-activated Cl currents in ZI cells revealed two types of receptor-coupled channel properties: one comprising short-lasting openings, high affinity for GABA, and low sensitivity to diazepam, and the other with long-lasting openings, low affinity for GABA, and high sensitivity to diazepam. Both types of channel activity were found in the same cell. Channel kinetics were well modeled by fitting dwell time distributions to biliganded activation and included two open and five closed states. We propose that short- and long-lasting openings correspond to GABA_A receptor/Cl channels containing 412 and 512 subunits, respectively.

Key words: GABA_A receptors; zolpidem; oxonol; FACS; development; rat; hippocampus

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19124921-17$05.00/0

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