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

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 GABA(A) receptors (GABA(A)Rs). Here, we studied whether distinct GABA(A)R subtypes mediate these various forms of inhibition using as approach mice carrying a point mutation in the alpha-subunit rendering individual GABA(A)R subtypes insensitive to diazepam without altering their GAB(A) 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 subunits containing GABA(A)Rs to phasic and tonic forms of inhibition. Fast phasic currents were mediated by synaptic alpha 2-GABA(A)Rs on the soma and by synaptic alpha 1-GABA(A)Rs on the dendrites. No contribution of alpha 3- or alpha 5-GABA(A)Rs was detectable. Slow phasic currents were produced by both synaptic and perisynaptic GABA(A)Rs, judged by their strong sensitivity to blockade of GABA reuptake. In the CA1 area, but not in the subiculum, perisynaptic alpha 5-GABA(A)Rs contributed to slow phasic currents. In the CA1 area, the diazepam-sensitive component of tonic inhibition also involved activation of alpha 5GABA(A)Rs 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 GABA(A)Rs subtypes.