A Mouse Kindling Model of Perimenstrual Catamenial Epilepsy

Abstract

Catamenial epilepsy is caused by fluctuations in progesteronederived GABA A receptor-modulating anticonvulsant neurosteroids, such as allopregnanolone, that play a significant role in the pathophysiology of epilepsy. However, there is no specific mouse model of catamenial epilepsy. In this study, we developed and characterized a mouse model of catamenial epilepsy by using the neurosteroid-withdrawal paradigm. It is hypothesized that seizure susceptibility decreases when neurosteroid levels are high (midluteal phase) and increases during their withdrawal (perimenstrual periods) in close association with GABA A receptor plasticity. A chronic seizure condition was created by using the hippocampus kindling model in female mice. Elevated neurosteroid levels were induced by sequential gonadotropin treatment, and withdrawal was induced by the neurosteroid synthesis inhibitor finasteride. Elevated neurosteroid exposure reduced seizure expression in fully kindled mice. Fully kindled mice subjected to neurosteroid withdrawal showed increased generalized seizure frequency and intensity and enhanced seizure susceptibility. They also showed reduced benzodiazepine sensitivity and enhanced neurosteroid potency, similar to the clinical catamenial seizure phenotype. The increased susceptibility to seizures and alterations in antiseizure drug responses are associated with increased abundance of the ␣4 and ␦ subunits of GABA A receptors in the hippocampus. These findings demonstrate that endogenous neurosteroids protect against seizure susceptibility and their withdrawal, such as that which occurs during menstruation, leads to exacerbation of seizure activity. This is possibly caused by specific changes in GABA A receptor-subunit plasticity and function, therefore providing a novel mouse model of human perimenstrual catamenial epilepsy that can be used for the investigation of disease mechanisms and new therapeutic approaches.

Estrous Cycle Regulation of Extrasynaptic δ-Containing GABAA Receptor-Mediated Tonic Inhibition and Limbic Epileptogenesis

“…However, there is evidence that cyclical fluctuations in steroid hormones across the estrous cycle regulate several GABA A R subunits (Maguire et al, 2005;Gangisetty and Reddy, 2010;Reddy et al, 2012). Previous studies reported that compared with estrus, the diestrus d-subunit is increased, the g2-subunit is decreased, and the a4-subunit exhibits no change (Maguire et al, 2005).…”

“…In perimenstrual catamenial epilepsy, evidence suggests that progesterone level changes play a key role in seizure exacerbations (Reddy, 2009;Reddy et al, 2012). Greater seizure activity within estrus is demonstrated in the hippocampus kindling model of epileptogenesis (Fig.…”

“…Because neurosteroids influence inhibition, behavioral and learning deficits observed during puberty are linked to changes in d-containing GABA A Rs (Shen et al, 2007(Shen et al, , 2010. Ovarian cycle-linked fluctuations in progesterone and neurosteroids have been proposed to alter GABA A R-mediated tonic inhibition (Maguire et al, 2005;Gangisetty and Reddy, 2010;Reddy et al, 2012). However, there is little information on molecular mechanisms by which GABA A R subunit composition and function in hippocampus subfields are regulated by the ovarian cycle.…”

“…To investigate whether the cycle-related plasticity of GABA A Rs mediating phasic and tonic inhibition affects neuronal network excitability in a seizure model, we studied the susceptibility of mice to epileptogenesis in rapid hippocampus kindling (Reddy and Mohan, 2011;Reddy et al, 2012). The progression of rate of kindling, electrographic mean AD threshold, and cumulative AD activity time for kindling criterion were recorded as main indices of epileptogenesis (Fig.…”

“…Fluctuations in steroid hormones, deficits in their cyclical availability, and receptor plasticity play a central role in susceptibility to menstrual conditions such as premenstrual syndrome, migraine, and catamenial epilepsy (Backstrom et al, 2003;Reddy, 2009). Catamenial epilepsy is characterized by seizures that cluster most often during the perimenstrual or periovulatory period, when progesterone levels are low (Herzog and Frye, 2003;Herzog et al, 2004Herzog et al, , 2011Reddy et al, 2012). However, the molecular mechanisms underlying these changes remain unclear.…”