A Mouse Hippocampus Kindling Model of Catamenial Epilepsy
Abstract number :
1.021
Submission category :
1. Translational Research
Year :
2011
Submission ID :
14435
Source :
www.aesnet.org
Presentation date :
12/2/2011 12:00:00 AM
Published date :
Oct 4, 2011, 07:57 AM
Authors :
D. S. Reddy, J. Gould, O. Gangisetty
Rationale: Catamenial epilepsy is a cyclical seizure condition that is often associated with an increase in seizures during the perimenstrual period. It affects a significant proportion of women with epilepsy. Catamenial seizures are caused by fluctuations in hormonal factors, especially neurosteroids, which modulate the function of synaptic and extrasynaptic GABA-A receptors; the neurosteroid withdrawal such as that occurs during menstruation causes increased excitability, where as elevated neurosteroid levels during luteal phase promote resistance to seizures. Neurosteroids such as allopregnanolone that are potent anticonvulsants, therefore, plays a significant role in the pathophysiology of catamenial epilepsy. It is hypothesized that seizure susceptibility decreases when neurosteroid levels are high (mid-luteal phase), and increases during their withdrawal (perimenstrual periods) in close association with specific changes in GABA-A receptor subunits expression in the hippocampus. The main objective of this study was to characterize a mouse hippocampus kindling model of catamenial epilepsy using the neurosteroid withdrawal approach. Methods: A chronic seizure condition was created using the hippocampus kindling model in adult female mice. The effect of elevated neurosteroids, induced endogenously by sequential gonadotropin regimen, was assessed by recording of three key parameters: (i) behavioral seizure stage; (ii) seizure duration; and (iii) afterdischarge duration. Neurosteroid withdrawal was induced by blocking neurosteroid synthesis in the brain by treatment with finasteride, a neurosteroid synthesis inhibitor. The TaqMan assay was used for quantification of GABA-A receptor subunit expression. Results: Daily kindling stimulation was associated with a steady progression of seizure activity. Mice reached the fully kindled state with consistent stage 5 seizures after ~14 stimulations. Our results shows that fully-kindled mice undergoing neurosteroid withdrawal have increased generalized seizure frequency and intensity; enhanced seizure susceptibility; and, similar to the clinical catamenial seizure phenotype, reduced benzodiazepine sensitivity and enhanced neurosteroid potency. The increased susceptibility to seizures and alterations in antiseizure drug responses are associated with increased abundance of the ? and ?4 subunits of GABA-A receptors in the hippocampus. Further, chronic neurosteroid exposure, induced endogenously by gonadotropin regimen that simulates the luteal phase, caused reduced seizure susceptibility, implicating ovarian neurosteroids in regulating catamenial seizures. Conclusions: These findings demonstrate that endogenous neurosteroids protect against seizure susceptibility and their withdrawal such as that occurs during menstruation leads to exacerbation of seizure activity, providing a potential mouse model that has features of human catamenial epilepsy. ** Supported by NIH grant NS051398 **
Translational Research