Early life adversity accelerates epileptogenesis and enhances depression-like behaviors in rats

Objective: Early life stressors are well-established risk factors for psychiatric disorders, and evidence also suggests that these promote vulnerability to epilepsy. Given the high prevalence of psychiatric disorders in epilepsy, early life stress may represent a common driver for these comorbidities. We used animal modelling to investigate the effects of early life stress on epileptogenesis and depressive behaviors, also exploring HPA axis programming as a potential associative mechanism. Methods: From post-natal day 2–9, Wistar rat dams (n = 3) and their offspring were exposed to the Limited Bedding and Nesting (LBN) model of early life adversity. Control dams (n = 3) were undisturbed. Maternal care was video-recorded, and behavior scored. As adults, rats (n = 7/group) underwent kainic acid-induced status epilepticus (SE), to trigger epilepsy development. Spontaneous seizures, depression-like behavior and HPA axis function were quantified. Results: LBN significantly altered aspects of maternal care, including markedly reducing the consistency of care (p < 0.05), compared to control conditions. Following SE, LBN rats exhibited significantly accelerated epileptogenesis (p = 0.01) and greater disease severity (p = 0.001), compared to control rats. Anhedonia and behavioral despair were observed in epileptic rats exposed to LBN. LBN rats showed significantly dampened HPA axis responsivity, but epileptic rats showed greater corticosterone responses to CRH administration (all p < 0.05). Significance: Early life adversity promotes a vulnerability to experimental epileptogenesis. These two ‘hits’ (early life stress and epilepsy) interact to create a depressive-like phenotype, but effects on HPA axis are complex and contrasting. This has implications for the mechanisms underpinning the increased prevalence of psychiatric disorders observed in people with epilepsy.