Abstracts

Rationale: Cortical dysplasia (CD) is a malformation of cortical development that is often associated with drug-resistant epilepsy and aberrant signaling of the PI3K-mTOR growth pathway. Previous studies in our lab using a mouse model of CD [the neuronal subset-specific conditional knockout of PTEN (NS-PTEN KO)] with hyperactive PI3K-mTOR signaling revealed abnormal epileptiform activity in these mice. Pharmacological inhibition of mTOR with rapamycin attenuated the epileptiform activity, suggesting a role for the mTOR pathway in the regulation of neuronal excitability. However, the underlying molecular mechanism for how aberrant PI3K-mTOR signaling contributes to the epilepsy phenotype in CD is unknown. Voltage-gated ion channel dysregulation is frequently associated with epilepsy, and more recently, evidence for mTOR-dependent regulation of ion channels under physiological conditions has been shown. In the current study, we evaluated whether aberrant PI3K-mTOR signaling in a model of CD contributes to altered expression of voltage-gated ion channels. Methods: NS-PTEN KO and wildtype (WT) mice at postnatal week 6 were used for evaluation of ion channel protein levels. In parallel, a subset of animals was treated with rapamycin (10 mg/kg) or vehicle by intraperitoneal injections for 5 days/week during postnatal weeks 4 and 5. We used Western blotting to measure protein levels of Kv1.1, Kv1.2, Kv1.4, Kv4.2, Kv4.3, and HCN1 in whole hippocampal homogenates. Results: Our results reveal a significant increase in the protein levels of Kv1.1 and a significant decrease in the levels of Kv1.2, Kv4.2, and HCN1 in the NS-PTEN KO compared littermate WT mice. There were no significant changes in the levels of Kv1.4 and Kv4.3. Rapamycin restored Kv1.1 protein levels in the NS-PTEN KO mice back to WT basal levels, but had no effect on the other ion channels that we evaluated (p<0.05, n=7-8 per group). Conclusions: Our findings reveal altered expression of voltage-gated ion channels in NS-PTEN KO mice, which may contribute to the epilepsy phenotype. Furthermore, our findings reveal a novel link between PI3K-mTOR dysregulation and Kv1.1 remodeling in the NS-PTEN KO model of CD. Future studies will evaluate cellular and subcellular localization of Kv1.1 dysregulation in this model.