Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by δ subunit-containing GABA _A receptors

Abstract

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...

Steroid withdrawal in the mouse results in anxiogenic effects of 3α,5β-THP: a possible model of premenstrual dysphoric disorder

“…Furthermore, fluctuations in circulating levels of THP have been shown to alter expression of the δ subunit (Sundstrom-Poromaa et al 2002;Lovick et al 2005;Maguire et al 2005). Although αβδ GABAR have been shown to exhibit an increased sensitivity to modulation by steroids (Wohlfarth et al 2002;Stell et al 2003), conflicting reports exist (Zhu et al 1996), and posttranslational mechanisms, such as receptor phosphorylation, are required for steroid modulation (Fancsik et al 2000;Harney et al 2003;Leidenheimer and Chapell 1997;Vicini et al 2002). In addition, steroid potentiation of α4βδ GABAR increases receptor efficacy (Bianchi and Macdonald 2003), which increases the rate and extent of receptor desensitization.…”

Molecular Targets for Antiepileptic Drug Development

“…25 The emerging understanding of the different roles of phasic and tonic inhibition in epileptic phenomena may suggest improved approaches to targeting GABA A receptors for epilepsy therapy. 204 For example, neuroactive steroids selectively target GABA A receptors containing ␦ subunits that mediate tonic inhibition 205,206 (TABLE 5). They may have reduced liability to tolerance 207 and may be useful in specific epilepsy syndromes, such as infantile spasms, or to treat hormone-dependent seizure exacerbations, such as in catamenial epilepsy.…”

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

“…In contrast, tonic inhibition is caused by low ambient GABA levels acting predominantly on extrasynaptic GA-BA A Rs. Since the anxiolytic effects of EtOH and neurosteroids have been attributed to a selective enhancement of tonic GABA inhibition, [19][20][21] we wondered whether an endogenous increase in the tonic component might possibly account for the lowanxiety phenotype of dnActRIB mice. To address this issue, we performed whole-cell recordings from adult CA1 pyramidal cells in slices from wt and tg mice.…”