Abstracts

Rationale: The neuroendocrine stress response is chronically dysregulated in patients with epilepsy, potentially contributing to both disease progression and the development of psychiatric comorbidities (Kanner 2003). Indeed, 40% of epilepsy patients suffer from stress- related psychopathologies such as anxiety and depression (Kanner et al. 2012). Whether neuroendocrine dysregulation and psychiatric comorbidities reflect direct effects of epilepsy-related pathologies, or secondary effects of disease burden particular to humans with epilepsy (i.e. social estrangement, employment changes) is not clear. Animal models provide an opportunity to dissociate these factors. Therefore, we queried whether and when epileptic mice would reproduce neuroendocrine and behavioral changes associated with human epilepsy.Methods: Male FVB mice (n=16) received 350 mg/kg of pilocarpine to induce status epilepticus (SE). Controls received saline (n=17). Baseline corticosterone (CORT) levels where measured at 1, 7 and 10 weeks post-SE. At 10 weeks mice (n=9/group) underwent sucrose preference, open field and the elevated plus maze tests. A second cohort of mice (n=7-8/group) were exposed to a 30 min restraint challenge and plasma samples were collected at 0, 30, 60 and 120 min, after which animals were killed and brains analyzed for Fos expression in known stress-regulatory regions.Results: Epileptic mice exhibited decreased sucrose preference, consistent with anhedonic depressive-like behaviors (p<0.05). Epileptic mice also avoided the center of an open field and spent less time in the open arms of the elevated plus maze (p<0.01). Epileptic mice had elevated morning baseline CORT at 5, 7 and 10 weeks post-SE (p<0.05). Increased CORT was accompanied by an increase in adrenal gland size (p<0.05). Exposure to restraint stress resulted in hyper-secretion of CORT at the 30 min time-point (p<0.05). Anatomical analysis revealed reduced Fos expression in infralimbic and prelimbic pre-frontal cortex, basolateral amygdala and all hippocampal subfields (dentate gyrus, CA1 and CA3) (p<0.001 for all Fos comparisons). No differences in Fos immunoreactivity were found in the paraventricular nucleus of the hypothalamus or central amygdala.Conclusions: Together these data demonstrate that epileptic mice develop a profound anxiety-like and depressive-like behavioral phenotype. These behavioral changes occur concomitantly with HPA axis dysfunction, characterized by increased adrenal drive and overall HPA axis hyperactivity. Notably, elevated CORT was first observed 5 days after SE, prior to the typical development of spontaneous seizures, indicating that neuroendocrine disruption precedes rather than follows the chronic phase of epilepsy in this model. Elevated CORT is sufficient to produce a depressive phenotype in animal models (Iijima 2010; Sterner 2010), and is associated with psychiatric comorbidities in humans (Pariante 2008), suggesting that neuroendocrine dysfunction produced by epileptogenic brain injuries may drive the development of comorbidities.