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

Abstract

CommentaryAllostasis is defined as the process by which the body responds to stressors in order to regain homeostasis, which involves proper functioning of the hypothalamic-pituitary-adrenal (HPA) axis. Allostatic load refers to the pathophysiological consequences of dealing with excessive, prolonged, or unresolved stress and is also thought to involve abnormalities in the functioning of the HPA axis (for a review, see [1]). There has been a great deal of speculation regarding the role of allostatic load in disease, and numerous correlational studies have attempted to investigate the pathological implications of allostatic load. However, as the authors state in the highlighted manuscript, "causality remains to be determined. "Through a series of studies, this group attempts to directly link allostatic load to pathophysiological outcomes. They previously demonstrated that social stress induces an allostatic load and vulnerability for depression in a subset of rats when faced with a subsequent, novel stressor (2). The authors suggest a "double-hit scenario" where the initial social defeat stressor (first hit) sensitizes a subset of animals, making them vulnerable to additional stressors (second hit). In the currently highlighted manuscript, Becker et al. extend these findings to investigate the pathophysiological implications of allostatic load acquired by exposure to a social defeat stress on epilepsy and associated comorbidities. This study, which is the basis of this Commentary, proposes that previous exposure to a stressor, which itself is insufficient to induce depression-like behavior, can alter epileptogenesis and predispose a subset of animals for associated comorbidities, including depression-like behaviors and cognitive impairments.Stress has been implicated in epilepsy given that the majority of patients report that stress either triggers or worsens their seizures (3). 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]). However, these studies focus on how acute and prolonged stress or exposure to glucocorticoids can alter neuronal excitability and seizure susceptibility with little regard to how changes in the functioning of the HPA axis may influence epilepsy.A large body of evidence suggests that early life stress can reprogram the H...

Impact of Stress on Epilepsy: Focus on Neuroinflammation—A Mini Review

“…These findings are consistent with the idea that chronic stress and depression in rodents results in worse epilepsy outcomes. Two papers published in 2015 provide more detailed information on stress-induced vulnerability to epilepsy and comorbid depression [ 24 , 26 ]. For instance, social defeat stress, followed by kainic acid-induced SE four weeks later, resulted in 50% of rats displaying a shorter latency to SE, accelerated epileptogenesis, and once epilepsy was induced, depressive-like behavior and cognitive deficits.…”

“…Their results suggested a “two-hit scenario”, where the initial social defeat stressor (first hit) sensitizes a subset of rats, making them vulnerable to additional insults (second hit) [ 24 ]. Based on these findings, Maguire [ 26 ] proposed a model whereby exposure to previous stressors induces HPA axis hyperresponsiveness in a subset of animals; resulting in vulnerability when subjected to a “second hit,” at which time pathological consequences resulted in depressive-like behaviors and increased seizure susceptibility.…”

“…The immune system plays a very prominent role in linking stress with depression [ 19 , 20 , 21 , 22 , 23 ]. Exposure to stress can sensitize or prime the inflammatory response to a subsequent insult, e.g., seizures, predisposing individuals to psychiatric comorbidities such as depression [ 24 , 25 , 26 ]. Numerous proinflammatory pathways are activated in depressed humans and stressed animals, including the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, which is constitutively expressed in immune cells such as microglia and other myeloid cells [ 18 , 20 , 23 ].…”