Signaling mechanisms underlying epilepsy and autism comorbidity

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One of the most susceptible periods in life to experience seizures is during the neonatal period. Seizures during this sensitive period can result in cognitive and behavioral impairments later in life. Specifically, early life seizures have shown to lead to the development of autistic-like behaviors. There have been many proposed mechanisms that describe the changes to the brain following seizures that have led to important advancements regarding therapeutics for epilepsy. However, approximately one third of individuals with epilepsy are resistant to pharmaceutical treatment options. Both inflammatory processes and the PI3K/AKT/mTOR pathway have been shown to play a role in the comorbidities associated with epilepsy, specifically autistic-like behavior. However, how the immune system and the mTOR signaling cascade interact to contribute to seizures and subsequent behavioral impairments is unknown. This study will investigate the mechanistic link between seizures during the neonatal period and the development of autistic-like behavior in mice. On postnatal day (PD) 10, male and female C57BL/6J mice will be given kainic acid to induce status epilepticus followed by administration of minocycline, rapamycin, or a combined treatment of both, one hour and 24 hours following status epilepticus. On PD12 and PD15, tissue will be collected for hippocampal cytokine analysis with RT-qPCR, Western blotting with hippocampal and cortical tissue to examine proteins in the PI3K/AKT/mTOR pathway, and immunohistochemistry to examine changes in astrocyte and microglia reactivity. A separate cohort of mice will go through the same early life seizure and treatment paradigm on PD10 and PD11, followed by examination of autistic-like behavioral changes. We will examine changes in communication, social behavior, repetitive behavior, learning and memory, anxiety, locomotor activity, and electrographic activity. The impact of minocycline, rapamycin, and the combined treatment on autistic-like behavior will help elucidate a possible mechanism for how characteristics of those with autism develop following early life seizures. Inhibiting the neuroinflammatory component of seizures could serve as an alternative treatment for those that suffer from seizures early in life, with hopes to minimize long-term behavioral comorbidities and epilepsy.