The proper functioning of the adult mammalian brain relies on the orchestrated regulation of neural activity by a diverse population of GABA (gamma-aminobutyric acid)-releasing neurons. Until recently, our appreciation of GABA-mediated inhibition focused predominantly on the GABA(A) (GABA type A) receptors located at synaptic contacts, which are activated in a transient or 'phasic' manner by GABA that is released from synaptic vesicles. However, there is growing evidence that low concentrations of ambient GABA can persistently activate certain subtypes of GABA(A) receptor, which are often remote from synapses, to generate a 'tonic' conductance. In this review, we consider the distinct roles of synaptic and extrasynaptic GABA receptor subtypes in the control of neuronal excitability.

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Neuroactive steroids are potent modulators of ␥-aminobutyric acid type A receptors (GABA ARs), and their behavioral effects are generally viewed in terms of altered inhibitory synaptic transmission. Here we report that, at concentrations known to occur in vivo, neuroactive steroids specifically enhance a tonic inhibitory conductance in central neurons that is mediated by extrasynaptic ␦ subunit-containing GABAARs. The neurosteroid-induced augmentation of this tonic conductance decreases neuronal excitability. Fluctuations in the circulating concentrations of endogenous neuroactive steroids have been implicated in the genesis of premenstrual syndrome, postpartum depression, and other anxiety disorders. Recognition that ␦ subunit-containing GABAARs responsible for a tonic conductance are a preferential target for neuroactive steroids may lead to novel pharmacological approaches for the treatment of these common conditions. hippocampus ͉ cerebellum ͉ neurosteroids ͉ inhibitory postsynaptic currents ͉ ␦ knockout mice G ABA A Rs (␥-aminobutyric acid type A receptors) are pentameric proteins that form Cl Ϫ -permeable ion channels activated by the neurotransmitter GABA. To date, 19 mammalian GABA A subunit isoforms have been identified, and these assemble to produce the dozen or so different receptor subtypes most frequently found in the brain (1). The most potent positive endogenous modulators of GABA A R function are the 3␣-hydroxy ring A-reduced pregnane steroids, that have sedativehypnotic, anticonvulsant, and anxiolytic effects (2-4). Severe mood disorders that can occur during the menstrual cycle and after pregnancy are suggested to involve alterations in the function of synaptic GABA A Rs (2, 3, 5) triggered by rapid decreases in the concentrations of these progesterone-derived neuroactive steroids (6).Recently, it has become apparent that distinct GABA A Rs participate in two types of inhibitory control. Transient activation of synaptic GABA A Rs is responsible for conventional phasic inhibition, whereas the continuous activation of extrasynaptic GABA A Rs can generate a form of tonic inhibition (7-14). GABA A Rs containing the ␦ subunit are restricted to extrasynaptic locations (15) and have an unusually high affinity for GABA (16,17), making them likely mediators of the tonic GABA A conductance recorded in both cerebellar (7,8) and dentate gyrus granule cells (DGGC) (10, 11). In mice lacking the ␦ subunit of the GABA A R, the effects of neuroactive steroids are greatly reduced (18). Moreover, recent reports (17,19,20) have raised the possibility that the steroid sensitivity of ␦ subunitcontaining GABA A Rs may be much higher than previously thought (21). In light of these findings, and the possible involvement of ␦ subunit-containing receptors in generating tonic conductances (8-11), we recorded from wild-type and ␦Ϫ͞Ϫ mice, and examined the effects of the naturally occurring neuroactive steroid 3␣,21-dihydroxy-5␣-pregnan-20-one (allotetrahydrodeoxycorticosterone, THDOC) on the tonic GABA A R-mediated conduct...

I To investigate the origin and functional significance of a recently described tonic GABAA receptor-mediated conductance in cerebellar granule cells we have made recordings from cells in cerebellar slices from rats of different ages (postnatal days P4 to P28). 2. During development there was a dramatic change in the properties of GABA-mediated synaptic transmission. The contribution to GABAA receptor-mediated charge transfer from the tonic conductance (GGABA), relative to that resulting from discrete spontaneous postsynaptic currents (sPSCs), was increased from 5 % at P7 to 99 % at P21. GGABA was reduced by bicuculline, tetrodotoxin and by lowering extracellular Ca2+, and was initially present only in those cells which exhibited sPSCs. 3. At P7 sPSCs were depolarizing, occasionally triggering a single action potential. By P18 the GABA reversal potential was shifted close to the resting potential and GGABA produced a shunting inhibition. Removal of GGABA by bicuculline increased granule cell excitability in response to current injection. 4. This novel tonic inhibition is present despite the low number of Golgi cell synapses on individual granule cells and appears to result from 'overspill' of synaptically released GABA leading to activation of synaptic and extrasynaptic GABAA receptors.