Stress is among the most frequently self-reported factors provoking epileptic seizures in children and adults. It is still unclear, however, why some people display stress-sensitive seizures and others do not. Recently, we showed that young epilepsy patients with stress-sensitive seizures exhibit a dysregulated hypothalamic-pituitaryadrenal (HPA)-axis. Most likely, this dysregulation gradually develops, and is triggered by stressors occurring early in life (early-life stress [ELS]). ELS may be particularly impactful when overlapping with the period of epileptogenesis. To examine this in a controlled and prospective manner, the present study investigated the effect of repetitive variable stressors or control treatment between postnatal day (PND) 12 and 24 in male mice exposed on PND10 to hyperthermia (HT)-induced prolonged seizures (control: normothermia). A number of peripheral and central indices of HPAaxis activity were evaluated at pre-adolescent and young adult age (ie, at PND25 and 90, respectively). At PND25 but not at PND90, body weight gain and absolute as well as relative (to body weight) thymus weight were reduced by ELS (vs control), whereas relative adrenal weight was enhanced, confirming the effectiveness of the stress treatment. Basal and stress-induced corticosterone levels were unaffected, though, by ELS at both ages. HT by itself did not affect any of these peripheral markers of HPA-axis activity, nor did it interact with ELS. However, centrally we did observe age-specific interaction effects of HT and ELS with regard to hippocampal glucocorticoid receptor mRNA expression, neurogenesis with the immature neurone marker doublecortin and the number of hilar (ectopic) granule cells using Prox1 staining. This 2 of 15 | UMEOKA Et Al.
| INTRODUC TI ONApproximately 50% of all children and adults with epilepsy acknowledge stress as a seizure-provoking factor, 1,2 ranking stress among the most frequently self-reported precipitants of seizures. 2-10 Why some individuals show stress-sensitivity in seizure activity and others do not still remains unclear. One explanation could be that the former as opposed to the latter group responds differently to stress as, for example, reflected by aberrant hypothalamic-pituitary-adrenal (HPA) activation or downstream targets after stress. In accordance, recent evidence obtained in a cohort of children and adolescents (6-17 years of age) with epilepsy indicated that those with stress-sensitive compared to individuals with stress-insensitive seizures or healthy controls show a blunted cortisol response to experimentally induced stress. 11Possibly, this renders hormonal negative-feedback actions on the brain less adequate, which could result in increased levels of proexcitatory central stress hormones such as corticotrophin-releasing hormone. 12 Which elements of the stress system become aberrant at specific developmental stages is not easy to investigate in humans with stress-sensitive seizures because this would require prospective longitudinal investigation of both centr...