Suppression of PIK3CA-driven epileptiform activity by acute pathway control

A significant proportion of epilepsy patients is non-responsive to conventional anti-seizure medications. Many of these patients harbor causative mutations in the PI3K-AKT-MTOR signaling pathway 1-5. Understanding mutation-specific pathophysiology is critical for developing molecularly targeted therapies. Here we identify physiological mechanisms underlying dysregulation of neuronal excitability and its acute attenuation in a mouse model expressing patient-related activating mutation in Pik3ca, that encodes the p110 catalytic subunit of PI3K 6. We show that Pik3ca-dependent hyperexcitability in hippocampal pyramidal neurons is mediated by changes in non-synaptic, cell-intrinsic properties, involving calcium and potassium channels. Our results also suggest a potential reason behind Pik3ca-dependent epileptic intractability. Further, we report that acute inhibition of PI3K or AKT, but not MTOR, suppresses the intrinsic epileptiform nature of the mutant neurons. This study therefore represents an important advance towards repurposing anti-cancer therapeutics to treat intractable epilepsy.