Abstracts

Rationale: here is a strong comorbidity between autism and epilepsy and one of the critical determinants of a child’s behavioral outcome in autistic spectrum disorders (ASD) is the onset of seizures. However, the link between seizures and ASD has received little attention, particularly in translational research using animal models of these disorders. Recent studies have shown that alteration of genes that modulate the mTOR signaling pathway result in an autistic behavioral phenotype. Methods: In order to examine whether early-life seizures alter social behavior and whether such alteration is through the mTOR signaling pathway, we administered kainate (2 mg/kg i.p.) to postnatal day 10 C57/BL6 mice to induce approximately 60 minutes of status epilepticus (SE). SE was then terminated by pentobarbital (10 mg/kg s.c.). The parallel control groups consisted of pentobarbital-treated animals and naïve mice. Male and female mice were both included to examine whether there was a sex-specific effect of early-life seizures on behavior. These mice were then processed through a battery of behavioral tests in adulthood: open field activity, elevated-plus maze, social partition, prepulse inhibition, and fear conditioning. At the conclusion of behavioral testing the brains were taken for western blotting analysis. The hippocampi from male and females were examined for down stream effectors of the PI3K/AKT/mTOR signaling pathway: phospho-S6, totalS6, phospho-AKT, and total AKT. Results: The experimental mice did not show any differences in open-field activity, elevated-plus maze, prepulse inhibition, and fear conditioning compared to control groups. However, female mice with early-life seizures spent much more time with an unfamiliar cagemate in a social partition test than the control groups (p < 0.01). This effect was not found in males. Female mice with early-life seizures also revealed enhanced phospho-S6 protein expression levels without alterations in the other downstream effectors, p < 0.001. Males with early-life seizures did not show changes in social behavior or altered protein expression for mTOR downstream effectors. Conclusions: These studies reveal gender-specific alterations in social behavior and mTOR pathway signaling following early-life seizures. These findings suggest the possibility that the effect of early-life seizures on social behavior in female mice may be mediated through mTOR signaling pathway. Future studies using mTOR pathway inhibitors will be useful in elucidating this possibility.