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J Neurophysiol (May 17, 2006). doi:10.1152/jn.01199.2005
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Submitted on November 10, 2005
Accepted on May 8, 2006

Specific subtypes of GABAA receptors mediate phasic and tonic forms of inhibition in hippocampal pyramidal neurons

George A Prenosil1, Edith M Schneider Gasser1, Uwe Rudolph1, Ruth Keist1, Jean-Marc Fritschy1, and Kaspar E Vogt1*

1 Institute for Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland

* To whom correspondence should be addressed. E-mail: kaspar.vogt{at}unibas.ch.

The main inhibitory neurotransmitter in the mammalian brain, {gamma}-aminobutyric acid (GABA), mediates multiple forms of inhibitory signals, such as fast and slow inhibitory postsynaptic currents and tonic inhibition, by activating a diverse family of ionotropic GABAA receptors (GABAARs). Here, we have investigated whether distinct GABAAR subtypes mediate these various forms of inhibition using as approach mice carrying a point mutation in the {alpha}-subunit rendering individual GABAAR subtypes insensitive to diazepam without altering their GABA-sensitivity and expression of receptors. Whole-cell patch-clamp recordings were performed in hippocampal pyramidal cells from single, double, and triple mutant mice. Comparing diazepam effects in knock-in and wild type mice allowed determining the contribution of {alpha}1, {alpha}2, {alpha}3, and {alpha}5 subunit containing GABAARs to phasic and tonic forms of inhibition. Fast phasic currents were mediated by synaptic {alpha}2-GABAARs on the soma and by synaptic {alpha}1-GABAARs on the dendrites. No contribution of {alpha}3- or {alpha}5-GABAARs was detectable. Slow phasic currents were produced by both synaptic and perisynaptic GABAARs, judged by their strong sensitivity to blockade of GABA reuptake. In the CA1 area, but not in the subiculum perisynaptic {alpha}5-GABAARs contributed to slow phasic currents. In the CA1 area the diazepam-sensitive component of tonic inhibition also involved activation of {alpha}5-GABAARs and slow phasic and tonic signals shared overlapping pools of receptors. These results demonstrate that the major forms of inhibitory neurotransmission in CA1 pyramidal cells are mediated by distinct GABAARs subtypes.




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