Perimenstrual-like hormonal regulation of extrasynaptic δ-containing GABAA receptors mediating tonic inhibition and neurosteroid sensitivity

Abstract

Neurosteroids are endogenous regulators of neuronal excitability and seizure susceptibility. Neurosteroids, such as allopregnanolone (AP; 3α-hydroxy-5α-pregnan-20-one), exhibit enhanced anticonvulsant activity in perimenstrual catamenial epilepsy, a neuroendocrine condition in which seizures are clustered around the menstrual period associated with neurosteroid withdrawal (NSW). However, the molecular mechanisms underlying such enhanced neurosteroid sensitivity remain unclear. Neurosteroids are allosteric modulators of both synaptic (αβδ2- containing) and extrasynaptic (αβγ2-containing) GABAA receptors, but they display greater sensitivity toward [1]-subunit receptors in dentate gyrus granule cells (DGGCs). Here we report a novel plasticity of extrasynaptic δ-containing GABAA receptors in the dentate gyrus in a mouse perimenstrual-like model of NSW. In molecular and immunofluorescence studies, a significant increase occurred inδ subunits, but notα1 ,α2 , β2 , and γ2 subunits, in the dentate gyrus of NSW mice. Electrophysiological studies confirmed enhanced sensitivity to AP potentiation of GABA-gated currents inDGGCs,but not inCA1pyramidal cells, inNSWanimals.APproduced a greater potentiation of tonic currents inDGGCs ofNSWanimals, and such enhancedAPsensitivity was not evident inδ-subunit knock-out mice subjected to a similar withdrawal paradigm. In behavioral studies, mice undergoingNSWexhibited enhanced seizure susceptibility to hippocampus kindling.APhas enhanced anticonvulsant effects in fully kindled wild-type mice, but notδ-subunit knock-out mice, undergoing NSW-induced seizures, confirmingδ-linked neurosteroid sensitivity. These results indicate that perimenstrualNSWis associated with striking upregulation of extrasynaptic,δ-containingGABAA receptors that mediate tonic inhibition and neurosteroid sensitivity in the dentate gyrus. These findings may represent a molecular rationale for neurosteroid therapy of catamenial epilepsy.