Neurosteroid modulation of synaptic and extrasynaptic GABA_A receptors

Certain naturally occurring pregnane steroids act in a nongenomic manner to potently and selectively enhance the interaction of the inhibitory neurotransmitter GABA with the GABA_A receptor. Consequently such steroids exhibit anxiolytic, anticonvulsant, analgesic, sedative, hypnotic, and anesthetic properties. In both physiological and pathophysiological scenarios, the pregnane steroids may function as endocrine messengers (e.g., produced in the periphery and cross the blood-brain barrier) to influence behaviour. However, additionally "neurosteroids" can be synthesised in the brain and spinal cord to act in a paracrine or autocrine manner and thereby locally influence neuronal activity. Given the ubiquitous expression of the GABA_A receptor throughout the mammalian central nervous system (CNS), physiological, pathophysiological, or drug-induced pertubations of neurosteroid levels may be expected to produce widespread changes in brain excitability. However, the neurosteroid/GABA_A receptor interaction is brain region and indeed neuron specific. The molecular basis of this specificity will be reviewed here, including (1) the importance of the subunit composition of the GABA_A receptor; (2) how protein phosphorylation may dynamically influence the sensitivity of GABA_A receptors to neurosteroids; (3) the impact of local steroid metabolism; and (4) the emergence of extrasynaptic GABA_A receptors as a neurosteroid target.