Disturbances of neuronal excitability changes during the ovarian cycle may elevate seizure frequency in women with catamenial epilepsy and enhance anxiety in premenstrual dysphoric disorder (PMDD). The mechanisms underlying these changes are unknown, but they could result from the effects of fluctuations in progesterone-derived neurosteroids on the brain. Neurosteroids and some anxiolytics share an important site of action: tonic inhibition mediated by delta subunit-containing GABA(A) receptors (deltaGABA(A)Rs). Here we demonstrate periodic alterations in specific GABA(A)R subunits during the estrous cycle in mice, causing cyclic changes of tonic inhibition in hippocampal neurons. In late diestrus (high-progesterone phase), enhanced expression of deltaGABA(A)Rs increases tonic inhibition, and a reduced neuronal excitability is reflected by diminished seizure susceptibility and anxiety. Eliminating cycling of deltaGABA(A)Rs by antisense RNA treatment or gene knockout prevents the lowering of excitability during diestrus. Our findings are consistent with possible deficiencies in regulatory mechanisms controlling normal cycling of deltaGABA(A)Rs in individuals with catamenial epilepsy or PMDD.

Fluctuating neurosteroid levels during the ovarian cycle modulate neuronal excitability through effects on GABAA receptors (GABAARs). The large increase in progesterone-derived neurosteroids during pregnancy and their precipitous decrease at parturition may have considerable effects on GABAARs during pregnancy and postpartum. Here we show a significant decrease in tonic and phasic inhibitions in pregnant mice, mediated by a downregulation of GABAAR δ and γ2 subunits, respectively. This decrease rebounds immediately postpartum. Mice with GABAAR δ subunit deficiencies (Gabrd+/− and Gabrd−/−), in which the rapid postpartum restoration of tonic inhibition is likely to be impaired, exhibit signs of depression-like and abnormal maternal behaviors resulting in reduced pup survival, that were ameliorated in Gabrd+/− mice by a selective agonist (THIP) of GABAARs containing δ subunits. Such mice constitute a novel mouse model of postpartum depression and have great potential for evaluating potential therapeutic interventions.

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.

The Rbfox family of RNA binding proteins regulates alternative splicing of many important neuronal transcripts but their role in neuronal physiology is not clear1. We show here that central nervous system (CNS)-specific deletion of the Rbfox1 gene results in heightened susceptibility to spontaneous and kainic acid-induced seizures. Electrophysiological recording reveals a corresponding increase in neuronal excitability in the dentate gyrus of the knockout mice. Whole transcriptome analyses identify multiple splicing changes in the Rbfox1−/− brain with few changes in overall transcript abundance. These splicing changes alter proteins that mediate synaptic transmission and membrane excitation, some of which are implicated in human epilepsy. Thus, Rbfox1 directs a genetic program required in the prevention of neuronal hyperexcitation and seizures. The Rbfox1 knockout mice provide a new model to study the post-transcriptional regulation of synaptic function.