title: A mouse kindling model of perimenstrual catamenial epilepsy.
abstract: Catamenial epilepsy is caused by fluctuations in progesterone-derived 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 α4 and δ 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.
authors.affiliation: Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M University Health Science Center, 8447 State Highway 47, MREB Building Room 1005, Bryan, TX 77807-3260, USA. reddy@medicine.tamhsc.edu
authors.forename: Doodipala Samba
authors.initials: DS
authors.lastname: Reddy
authors.forename: Jordan
authors.initials: J
authors.lastname: Gould
authors.forename: O
authors.initials: O
authors.lastname: Gangisetty
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology; D000818:Animals; D003975:Diazepam / Q000494:pharmacology; D004195:Disease Models, Animal; D004827:Epilepsy / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D018120:Finasteride / Q000494:pharmacology; D006062:Gonadotropins / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007696:Kindling, Neurologic / Q000502:physiology*; D008597:Menstrual Cycle / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011280:Pregnanolone / Q000097:blood; D011374:Progesterone / Q000097:blood; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D011963:Receptors, GABA-A / Q000235:genetics; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology
chemical_list: D058891:5-alpha Reductase Inhibitors; D006062:Gonadotropins; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D011374:Progesterone; D018120:Finasteride; D011280:Pregnanolone; D003975:Diazepam