Early postnatal stress confers enduring vulnerability to limbic epileptogenesis

Purpose: Early life stress has enduring behavioral and neuroendocrine effects, particularly in hippocampus and amygdala. This may be relevant to mesial temporal lobe epilepsy (MTLE) that arises from these structures. In rats, we tested the hypothesis that early postnatal stress, in the form of maternal separation (MS), creates vulnerability to limbic epileptogenesis in adult life. Methods: On postnatal days 2-14, we exposed male and female nonepileptic rats to either MS for 180 min/day, or early handling (EH) and brief separation (15 min/day). At 7 weeks of age, rats of both genders exposed to MS displayed significantly increased anxiety, as evidenced by reduced time spent in the open arms of the elevated plus maze compared with EH rats. For epileptogenesis experiments, separate cohorts of rats, similarly exposed to either early life MS or EH, were implanted with bipolar electrodes into the left amygdala and one week later rapid electrical kindling performed until fully kindled (five Class V seizures, Racine scale). Results: In females, fewer stimulations were required following MS than EH to reach the fully kindled state (39.6 +/- 6.4 vs. 67.1 +/- 9.4; p < 0.0001); no differences were observed in males (MS: 49.1 +/- 5.1; EH: 53.7 +/- 6.6 stimulations). Discussion: We conclude that, while postnatal MS stress increases anxiety in both genders, this early life stressor results in persisting vulnerability to limbic epileptogenesis only in females. This has implications for human MTLE and its psychiatric comorbidities, suggesting a common causation model and the involvement of gender-specific factors such as sex hormones.