Abstracts

Rationale: Currently available pharmacological anticonvulsant treatments employed to control seizures in children remain ineffective in over 30% of patients and also fail to attenuate disease progression. Additionally, these drugs produce cognitive, behavioral and mood altering side effects. Housing in an enriched environment (EE) has shown efficacy in ameliorating the detrimental effects of prolonged seizures in developing animals. Here, we investigated the ability of EE to mitigate seizure-induced microglia activation and behavioral deficits following kainate-induced status epilepticus (KA-SE) in young mice. Methods: P21 CX3CR1EGFP/+ transgenic mice were injected intraperitoneally with either Kainic acid (12mg/kg) or PBS and monitored for progression of seizures for at least one hour. After recovery, animals who experienced at least 30 minutes of continuous seizures were divided into two housing conditions: enriched environment (EE - 4 KA-injected and 4 PBS-injected mice housed in two large cages connected by tunnels and equipped with multiple toys and running wheels) and isolated (ISO - mice housed singly in standard cages). Behavior was assessed at 2 and 8 days post-KA-SE using the open field and elevated plus maze tests. Ten days after KA-SE (P31), mice were perfused and their brains collected for analysis. 40µm coronal sections containing the lateral septum, CA3 region of the hippocampus, and amygdala were mounted and quantified at 20x resolution. Results: Fluorescence microscopy revealed striking differences in microglial activation between mice housed in EE and ISO conditions. At P31, KA-EE mice showed no significant microglial activation relative to control (PBS-EE) mice. However, KA-ISO mice exhibited residual and heightened levels of microglial activation compared to KA-EE mice (p<0.003), with markedly increased clumping of microglia in the CA3 region. Similarly, significantly increased activation in the KA-ISO group was present in the lateral septum (p<.014) and amygdala (p<.004). While KA-ISO mice exhibited persistent deficits in exploratory behavior—as measured by open arm time in an elevated plus maze—relative to KA-EE littermates (p<.047) 8 days after seizure induction, EE produced a time-dependent reduction in behavioral impairments. Conclusions: We show that EE attenuates the detrimental effects of KA-induced seizure including inflammatory microglia response and behavioral impairment. Prior research has established microglia as key cellular mediators of neuroinflammatory processes, where activated microglia undergo rapid proliferation to facilitate efficient immune response and release inflammatory proteins such as cytokines and chemokines. Thus, by reducing microglia activation, the current data demonstrated the anti-inflammatory action of EE. The research revealed extensive protective effects of EE at both cellular and behavioral levels and proposes the therapeutic efficacy of EE in pediatric epilepsy patients.