Regulation of excitability by extrasynaptic GABA(A) receptors

Not only are GABA(A) receptors activated transiently by GABA released at synapses, but high affinity, extrasynaptic GABA(A) receptors are also activated by ambient, extracellular GABA as a more persistent form of signalling (often termed tonic inhibition). Over the last decade tonic GABA(A) receptor-mediated inhibition and the properties of GABA(A) receptors mediating this signalling have received increasing attention. Tonic inhibition is present throughout the central nervous system, but is expressed in a cell-type specific manner (e.g. in interneurons more so than in pyramidal cells in the hippocampus, and in thalamocortical neurons more so than in reticular thalamic neurons in the thalamus). As a consequence, tonic inhibition can have a complex effect on network activity. Tonic inhibition is not fixed but can be modulated by endogenous and exogenous modulators, such as neurosteroids, and by developmental, physiological and pathological regulation of GABA uptake and GABA(A) receptor expression. There is also growing evidence that tonic currents play an important role in epilepsy, sleep (also actions of anaesthetics and sedatives), memory and cognition. Therefore, drugs specifically aimed at targeting the extrasynaptic receptors involved in tonic inhibition could be a novel approach to regulating both physiological and pathological processes.