Specific Subtypes of GABA_AReceptors 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.

Tonic GABAA Receptors as Potential Target for the Treatment of Temporal Lobe Epilepsy

“…By targeting specific subunits, one could make use of the particular pharmacokinetic properties such as affinity, channel opening time, refractory period, etc., which would allow fine-tuning of neuronal activity in the presence of varying concentrations of antagonist or agonists [23, 24, 88, 132]. …”

Dendrite-targeting interneurons control synaptic NMDA-receptor activation via nonlinear α5-GABAA receptors

“…However, synaptic localization of these receptors has remained controversial 22–24 . While some studies using light microscopy indicated homogeneously distributed expression of α5-GABA A Rs along the (extrasynaptic) somatodendritic membrane of CA1 pyramidal cells 25,26 , others have suggested that these receptors are preferentially expressed in pyramidal-cell dendrites 23,27 . Furthermore, ultrastructural data suggested a specific enrichment in the postsynaptic membrane of hippocampal and neocortical pyramidal cells 23 .…”

Enhancement of Inhibitory Neurotransmission by GABA A Receptors Having α 2,3 -Subunits Ameliorates Behavioral Deficits in a Mouse Model of Autism

“…Receptors containing α 1 subunits mediate fast synaptic transmission at the synapses on distal dendrites, whereas receptors containing α 2 subunits mediate fast synaptic transmission at synapses on the soma (Prenosil et al, 2006). Different inputs impinge on CA1 pyramidal neurons at these sites, providing a potential mechanism for understanding how specific modulation of these two receptor types with L-838,417 and zolpidem leads to differential effects on spatial learning and sedation.…”

“…Different inputs impinge on CA1 pyramidal neurons at these sites, providing a potential mechanism for understanding how specific modulation of these two receptor types with L-838,417 and zolpidem leads to differential effects on spatial learning and sedation. Because GABA A receptors containing α 2 subunits have specific physiological roles (Prenosil et al, 2006) and drug actions on them do not induce tolerance (Vinkers et al, 2012), they provide an attractive molecular target for therapy of autism and other disorders with reduced GABAergic inhibitory neurotransmission.…”