The main inhibitory neurotransmitter in the mammalian brain, 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 studied whether distinct GABAAR subtypes mediate these various forms of inhibition using as approach mice carrying a point mutation in the α-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 α1, α2, α3, and α5 subunits containing GABAARs to phasic and tonic forms of inhibition. Fast phasic currents were mediated by synaptic α2-GABAARs on the soma and by synaptic α1-GABAARs on the dendrites. No contribution of α3- or α5-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 α5-GABAARs contributed to slow phasic currents. In the CA1 area, the diazepam-sensitive component of tonic inhibition also involved activation of α5-GABAARs and slow phasic and tonic signals shared overlapping pools of receptors. These results show that the major forms of inhibitory neurotransmission in hippocampal pyramidal cells are mediated by distinct GABAARs subtypes.
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