Specific Subtypes of GABAA Receptors Mediate Phasic and Tonic Forms of Inhibition in Hippocampal Pyramidal Neurons

Abstract

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 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 alpha1, alpha2, alpha3, and alpha5 subunits containing GABA(A)Rs to phasic and tonic forms of inhibition. Fast phasic currents were mediated by synaptic alpha2-GABA(A)Rs on the soma and by synaptic alpha1-GABA(A)Rs on the dendrites. No contribution of alpha3- or alpha5-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 alpha5-GABA(A)Rs contributed to slow phasic currents. In the CA1 area, the diazepam-sensitive component of tonic inhibition also involved activation of alpha5-GABA(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.

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

“…In addition to potentiating IPSCs, diazepam has been reported to augment the small tonic GABA current in CA1 pyramidal cells. 30 However, in contrast to its differential modulation of phasic inhibition, the diazepam-induced increase in holding current was not significantly different between CA1 pyramidal cells from wt hippocampi (11.1 ± 1.5 pA, n = 16) and dnActRIB hippocampi (10.3 ± 2.4 pA, n = 15, P = 0.76).…”

“…Recent evidence from CA1 pyramidal cells suggests indeed that, besides a5GABA A Rs, 30,38 a4GABA A Rs (combined with d-subunit) participate in tonic inhibition. 22 Since a4GABA A Rs are benzodiazepine-insensitive, their apparent upregulation in tg CA1 pyramidal cells (at the expense of benzodiazepine-sensitive GABA A Rs) could be in part responsible for the reduced diazepam sensitivity in tg CA1 pyramidal cells.…”

Molecular and functional heterogeneity of GABAergic synapses

“…Focusing on CA1 pyramidal cells, where α2-GABA A R predominate in the perisomatic area and the axon-initial segment [80,81], a pronounced reduction of gephyrin clusters was observed, notably on cell somata, on the axon-initial segment, as well as in stratum radiatum and stratum oriens (Fig. 3A).…”

Dendritic Inhibition Provided by Interneuron-Specific Cells Controls the Firing Rate and Timing of the Hippocampal Feedback Inhibitory Circuitry

“…Similar to findings obtained in PCs, inhibitory synapses onto interneurons may be composed of different GABA A receptor subunits (Hájos and Mody, 1997;Patenaude et al, 2001;Salesse et al, 2011). In particular, synaptic expression of the ␣5 GABA A receptor subunit (GABA A -␣5), which is responsible for kinetically slow IPSCs, has been reported in the CA1 hippocampus and in OLM interneurons (Loebrich et al, 2006;Prenosil et al, 2006;Ali and Thomson, 2008;Zarnowska et al, 2009;Salesse et al, 2011). The latter may explain a slower time course of uIPSCs in OLMs compared with BISs.…”