Physiological role for GABAA receptor desensitization in the induction of long-term potentiation at inhibitory synapses

Martin Field,Valentina Dorovykh,Trevor G Smart,Philip Thomas

doi:10.1038/s41467-021-22420-9

Martin Field, Valentina Dorovykh + Show 2 more

Open Access

https://doi.org/10.1038/s41467-021-22420-9

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Abstract

GABAA receptors (GABAARs) are pentameric ligand-gated ion channels distributed throughout the brain where they mediate synaptic and tonic inhibition. Following activation, these receptors undergo desensitization which involves entry into long-lived agonist-bound closed states. Although the kinetic effects of this state are recognised and its structural basis has been uncovered, the physiological impact of desensitization on inhibitory neurotransmission remains unknown. Here we describe an enduring form of long-term potentiation at inhibitory synapses that elevates synaptic current amplitude for 24 h following desensitization of GABAARs in response to agonist exposure or allosteric modulation. Using receptor mutants and allosteric modulators we demonstrate that desensitization of GABAARs facilitates their phosphorylation by PKC, which increases the number of receptors at inhibitory synapses. These observations provide a physiological relevance to the desensitized state of GABAARs, acting as a signal to regulate the efficacy of inhibitory synapses during prolonged periods of inhibitory neurotransmission.

Highlights

GABAA receptors (GABAARs) are pentameric ligand-gated ion channels distributed throughout the brain where they mediate synaptic and tonic inhibition
Cells were not subjected to electrophysiological recording during pre-treatment in order to avoid GABAAR rundown that is known to occur under such conditions[40,41,42], and which may obscure the induction of synaptic plasticity
No change was apparent in the interevent intervals (IEIs) of the IPSCs, suggesting no concomitant alteration occurs in presynaptic release probability or in network activity (Fig. 1c)

Summary

Introduction

GABAA receptors (GABAARs) are pentameric ligand-gated ion channels distributed throughout the brain where they mediate synaptic and tonic inhibition Following activation, these receptors undergo desensitization which involves entry into long-lived agonist-bound closed states. Recent structural work has shown that the key differences between this state and the agonist-bound open (conducting) state are conformational changes that occur at the ‘internal face’ of the receptor This involves rotation of the receptor’s transmembrane domain α-helices and a collapse of the internal portal of the ion channel to limit the transmembrane flux of ions[11,12,13,14,15]. This does not exclude the possibility that entry into the desensitized state can initiate long-term plasticity at inhibitory synapses

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