title: Early life maternal separation stress augmentation of limbic epileptogenesis: the role of corticosterone and HPA axis programming.
abstract: Early life stress causes long-lasting effects on the limbic system that may be relevant to the development of mesial temporal lobe epilepsy (MTLE) and its associated psychopathology. Recent studies in rats suggest that maternal separation (MS), a model of early life stress, confers enduring vulnerability to amygdala kindling limbic epileptogenesis. However, the mechanisms underlying this remain unknown. Here, we tested whether hypothalamic-pituitary-adrenal (HPA) axis hyper-reactivity induced by MS - specifically the excessive secretion of corticosterone following a seizure - was involved in this vulnerability. In adult female rats subjected to MS from postnatal days 2-14, seizure-induced corticosterone responses were significantly augmented and prolonged for at least two hours post-seizure, compared to control early-handled (EH) rats. This was accompanied by reduced seizure threshold (p<0.05) and increased vulnerability to the kindling-induced progression of seizure duration (p<0.05) in MS rats. Pre-seizure treatment with the corticosterone synthesis inhibitor, metyrapone (MET) (50mg/kgsc) effectively blocked seizure-induced corticosterone responses. When delivered throughout kindling, MET treatment also reversed the MS-induced reduction in seizure threshold and the lengthened seizure duration back to levels of EH rats. These observations suggest that adverse early life environments induce a vulnerability to kindling epileptogenesis mediated by HPA axis hyper-reactivity, which could have relevance for the pathogenesis of MTLE.
authors.affiliation: Department of Medicine, Royal Melbourne Hospital, Melbourne Brain Centre, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Amelia S
authors.initials: AS
authors.lastname: Koe
authors.affiliation: St Vincent's Mental Health Service, St Vincent's Hospital, Fitzroy, VIC, Australia; Department of Psychiatry, St Vincent's Hospital, University of Melbourne, Fitzroy, VIC, Australia.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Salzberg
authors.affiliation: Department of Pharmacology, University of New South Wales, Sydney, NSW, Australia.
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Morris
authors.affiliation: Department of Medicine, Royal Melbourne Hospital, Melbourne Brain Centre, University of Melbourne, Parkville, VIC, Australia; Department of Neurology, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Terence J
authors.initials: TJ
authors.lastname: O'Brien
authors.affiliation: Department of Medicine, Royal Melbourne Hospital, Melbourne Brain Centre, University of Melbourne, Parkville, VIC, Australia. Electronic address: ncjones@unimelb.edu.au.
authors.forename: Nigel C
authors.initials: NC
authors.lastname: Jones
mesh_terms: D000818:Animals; D003345:Corticosterone / Q000378:metabolism*; D004827:Epilepsy / Q000503:physiopathology*; D005260:Female; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism / Q000503:physiopathology*; D007696:Kindling, Neurologic / Q000502:physiology; D008016:Life Change Events; D008426:Maternal Deprivation; D010913:Pituitary-Adrenal System / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats; D013315:Stress, Psychological / Q000503:physiopathology*
chemical_list: D003345:Corticosterone
keywords: Corticosterone; Early life stress; Epilepsy; Epileptogenesis; HPA axis; Kindling; Metyrapone