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.

Interaction between sex and early-life stress: Influence on epileptogenesis and epilepsy comorbidities

“…Too many research groups are avoiding/neglecting the issue of examining sex effects in their studies, as is evident from inspection of Table 1. This is not only apparent in stress/epilepsy studies, but also many areas of neurology and psychiatry early life stress programming of HPA axis function can be ameliorated by early intervention (Ivy et al, 2010), or by intervention in adulthood (Koe et al, 2014;Weaver et al, 2005). This needs to be taken into account when designing mechanistic and treatment protocols regarding effects of early life stress on adult disease states.…”

“…The males in this study, but not the females also exhibited higher corticosterone levels, suggesting that this was related to the higher seizure scores and mortality. Finally, a study by Koe et al showed that female rats previously exposed to maternal separation demonstrated exaggerated corticosterone stress responses to kindled seizures, as well as a vulnerability to amygdala kindling (Koe et al, 2014). By blocking the synthesis of corticosterone, the authors were able to prevent the seizure-induced corticosterone response, and normalise kindling rates.…”

Primed for Problems: Stress Confers Vulnerability to Epilepsy and Associated Comorbidities

“…of the HPA axis (4). However, few studies have tackled the role of allostatic load in adult animals and the effect on HPA axis function and implications for disease.…”

“…Interestingly, recent studies demonstrated that seizures themselves activate the HPA axis (4,8), and seizure-induced elevations in corticosterone levels correlated with increased depression-like behaviors (9). It is possible that the "first hit" alters HPA axis reactivity, whereby in response to the "second hit, " there is hyperexcitability of the HPA axis that contributes to increased seizure susceptibility and associated comorbidities.…”

“…Consistent with a role of stress in epilepsy, the currently highlighted study demonstrates that in a subset of rats (~50%) previous exposure to social stress results in a reduced threshold to induce status epilepticus (SE), a shorter latency to SE, and increased seizure frequency in chronically epileptic rats (see Figure 3 in the Becker et al article). These results alone are not surprising, given the fact that stress has been demonstrated to increase seizure susceptibility in a variety of experimental epilepsy models (3) and has recently been demonstrated to accelerate epileptogenesis (4). Further, administration of exogenous stress hormones-including corticosterone and corticotropin-releasing hormone (CRH)-have been shown to exert proconvulsant actions in numerous experimental models of epilepsy (for a review, see [5]).…”