The Perimenstrual Delta Force: A Trojan Horse for Neurosteroid Effects

Abstract

CommentaryHormones influence neuronal excitability and seizure susceptibility in both adulthood and during development (1)(2)(3)(4)(5)(6)(7)(8). A paradigm illustrating these interactions is catamenial epilepsy, where seizures may cluster around specific periods of the menstrual cycle (3). The perimenstrual (C1) type of catamenial epilepsy is a type of epilepsy in which seizures cluster around the menstrual phase when estradiol, progesterone, as well as the neurosteroid allopregnanolone decline. Allopregnanolone is a progesterone metabolite known to act on GABA A receptors. Progesterone is converted to 5a-dihydroprogesterone (5a-DHP) by 5a-reductase, and then 5a-DHP is converted to allopregnanolone by 3b-hydroxysteroid dehydrogenase (3b-HSD).Reddy's team has been a pioneer in studies aiming to shed light in the molecular and pathophysiological mechanisms of increased seizure susceptibility in perimenstrual epilepsy. To recreate the hormonal and neurosteroid changes occurring during this perimenstrual period, they introduced a model of neurosteroid withdrawal (NSW) in adult female mice by administering high dose progesterone twice daily for 7 days followed by finasteride, a 5a-reductase inhibitor that blocks neurosteroid synthesis (8). This NSW model recreates high levels of allopregnanolone during the progesterone administration phase, which rapidly decline to normal levels during NSW. Interestingly, NSW mice demonstrate increased susceptibility to kindling associated with increased expression of the a4 GABA A receptor subunit in the dentate gyrus granule cells (8). The Carver et al. study completes these findings by showing a parallel increased expression of the d GABA A receptor subunit, a common partner of a4 in extrasynaptic GABA A receptors, as well as enhanced allopregnanolone potentiation of tonic but also phasic GABA A receptor currents in NSW mice. Such findings would be normally considered as capable of evoking antiseizure effects by increasing tonic inhibition. However, the authors found smaller tonic GABA current shifts in NSW granule cells compared to controls in the absence of added GABA, possibly suggesting the existence of silent GABA A receptors or low extracellular GABA in NSW hippocampus. In d knock-out 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 (αβγ2-containing) and extrasynaptic (αβδ-containing) GABA A receptors, but they display greater sensitivity toward δ-subunit receptors in dentate gyrus granule cells (DGGCs). Here we report a novel plasticity of extrasynaptic δ-containing GABA A receptors in the den...

Catamenial Epilepsy: Discovery of an Extrasynaptic Molecular Mechanism for Targeted Therapy

“…However, such selective overexpression of δGABA-A receptors is not sufficient to suppress the increased seizure susceptibility triggered by NSW in the absence of AP. Yet, this pathologic increase in δGABA-A receptors may act as a vehicle-catalyst (“Trojan horse”) for the exogenous AP to inhibit seizures ( Galanopoulou, 2015 ). Indeed, this special sensitivity to AP that women with perimenstrual epilepsy exhibit is in agreement with the findings from the NIH progesterone trial, in which the responder group was women with C1 catamenial epilepsy ( Herzog et al, 2012 ).…”

“…In a recent publication, we reported the unique plasticity of extrasynaptic δGABA-A receptors in the dentate gyrus of the hippocampus using a mouse perimenstrual model ( Reddy et al, 2012 ; Wu et al, 2013 ; Carver et al, 2014 ). A delta-force hypothesis was coined to explain this phenomenon ( Galanopoulou, 2015 ). In summary, the proposed mechanism poses that the perimenstrual decline in neurosteroids triggers the selective overexpression of δGABA-A receptors in the dentate gyrus granule cells, but this is not sufficient to suppress the increased seizure susceptibility of NSW mice in the absence of AP ( Figure 4 ).…”