GABA(A) (gamma-aminobutyric acid type A) receptors mediate most of the 'fast' synaptic inhibition in the mammalian brain and are targeted by many clinically important drugs. Certain naturally occurring pregnane steroids can potently and specifically enhance GABA(A) receptor function in a nongenomic (direct) manner, and consequently have anxiolytic, analgesic, anticonvulsant, sedative, hypnotic and anaesthetic properties. These steroids not only act as remote endocrine messengers, but also can be synthesized in the brain, where they modify neuronal activity locally by modulating GABA(A) receptor function. Such 'neurosteroids' can influence mood and behaviour in various physiological and pathophysiological situations, and might contribute to the behavioural effects of psychoactive drugs.

The principal inhibitory neurotransmitter in the mammalian brain, ␥-aminobutyric acid (GABA), is thought to regulate memory processes by activating transient inhibitory postsynaptic currents. Here we describe a nonsynaptic, tonic form of inhibition in mouse CA1 pyramidal neurons that is generated by a distinct subpopulation of GABA type A receptors (GABA ARs). This tonic inhibitory conductance is predominantly mediated by ␣5 subunit-containing GABAARs (␣5GABAARs) that have different pharmacological and kinetic properties compared to postsynaptic receptors. GABAARs that mediate the tonic conductance are well suited to detect low, persistent, ambient concentrations of GABA in the extracellular space because they are highly sensitive to GABA and desensitize slowly. Moreover, the tonic current is highly sensitive to enhancement by amnestic drugs. Given the restricted expression of ␣5GABAARs to the hippocampus and the association between reduced ␣5GABAAR function and improved memory performance in behavioral studies, our results suggest that tonic inhibition mediated by ␣5GABAARs in hippocampal pyramidal neurons plays a key role in cognitive processes. The ␥-aminobutyric acid (GABA) subtype A receptor (GABA A R) is a pentameric anion-selective ion channel that assembles from different classes of subunits (␣1-6, ␤1-3, ␥1-3, ␦, , , and ) (1). The combination of various GABA A R subunits confers different biophysical and pharmacological properties and regulates regional and subcellular patterns of distribution (2, 3). The subunit composition critically determines agonist affinity, receptor kinetics, and sensitivity to a variety of clinically important drugs, including benzodiazepines and general anesthetics.Studies of gene-targeted mice have implicated specific GABA A R subunit isoforms in critical aspects of information processing in the brain. Notably, ␣5-null mutant mice (␣5Ϫ͞Ϫ) exhibit improved performance in the water maze model of spatial learning, a hippocampus-dependent learning task (4). Further, mice carrying a point mutation at position 105 of the ␣5 subunit (H105R) experience an unexpected selective reduction of ␣5GABA A Rs in hippocampal pyramidal neurons and improved performance for learning tasks (5). Pharmacological studies further support the involvement of ␣5GABA A Rs in learning processes; for example, ␣5 subunit-selective inverse agonists such as L-655,708 enhance learning performance in rats in the Morris water maze test (6, 7). Moreover, ␣5 subunitselective inverse agonists exhibit desirable nootropic effects without causing adverse convulsant activities associated with nonselective GABA A R inverse agonists. Thus, inhibition of ␣5GABA A Rs presents an attractive strategy for developing memory-enhancing drugs.The neuronal substrates underlying improved cognitive performance associated with reduced ␣5GABA A R function remain unknown. The ␣5 subunit has a unique and limited pattern of distribution in the mammalian brain. Although ␣5-containing receptors constitute Ͻ5% of the total GABA A R population...

GABA is the principal inhibitory neurotransmitter in the CNS and acts via GABAAand GABABreceptors. Recently, a novel form of GABAAreceptor-mediated inhibition, termed “tonic” inhibition, has been described. Whereas synaptic GABAAreceptors underlie classical “phasic” GABAAreceptor-mediated inhibition (inhibitory postsynaptic currents), tonic GABAAreceptor-mediated inhibition results from the activation of extrasynaptic receptors by low concentrations of ambient GABA. Extrasynaptic GABAAreceptors are composed of receptor subunits that convey biophysical properties ideally suited to the generation of persistent inhibition and are pharmacologically and functionally distinct from their synaptic counterparts. This mini-symposium review highlights ongoing work examining the properties of recombinant and native extrasynaptic GABAAreceptors and their preferential targeting by endogenous and clinically relevant agents. In addition, it emphasizes the important role of extrasynaptic GABAAreceptors in GABAergic inhibition throughout the CNS and identifies them as a major player in both physiological and pathophysiological processes.