The impact of tonic GABAA receptor-mediated inhibition on neuronal excitability varies across brain region and cell type

Abstract

The diversity of GABAA receptor (GABAAR) subunits and the numerous configurations during subunit assembly give rise to a variety of receptors with different functional properties. This heterogeneity results in variations in GABAergic conductances across numerous brain regions and cell types. Phasic inhibition is mediated by synaptically-localized receptors with a low affinity for GABA and results in a transient, rapidly desensitizing GABAergic conductance; whereas, tonic inhibition is mediated by extrasynaptic receptors with a high affinity for GABA and results in a persistent GABAergic conductance. The specific functions of tonic versus phasic GABAergic inhibition in different cell types and the impact on specific neural circuits are only beginning to be unraveled. Here we review the diversity in the magnitude of tonic GABAergic inhibition in various brain regions and cell types, and highlight the impact on neuronal excitability in different neuronal circuits. Further, we discuss the relevance of tonic inhibition in various physiological and pathological contexts as well as the potential of targeting these receptor subtypes for treatment of diseases, such as epilepsy.

Keywords: GABA; epilepsy; neuronal excitability; neurosteroids; tonic inhibition.

Figure 1

Extrasynaptic GABA_ARs mediate tonic conductances in principal neurons and interneurons. Interneurons regulate the activity of principal cells through GABAergic transmission, but are in turn regulated by GABAergic input from other interneurons. This additional level of GABAergic signaling introduces complexity to understanding neuronal excitability and its modulation. For example, neurosteroids can act on GABA_ARs, especially extrasynaptic receptors that contain a δ subunit, to potentiate GABAergic inhibition on principal neurons and diminish their excitability. Simultaneously, neurosteroids can potentiate GABAergic inhibition on interneurons, thus disinhibiting the principal neurons and enhancing their excitability. These opposing effects, combined with the variability in GABAergic inhibition across cell types and brain regions, present complications when considering GABA_ARs as therapeutic targets.