Abdulkareem, A. F.; Elste, N. H.; Younger, R.; Prina, M. L.; Dennis, E.; Urbanczyk, J.; Bayat, M.; Malik, H. A.; Tafti, S. A.; Holoubek, H. S.; Marchand, D.; Beenken, K. E.; Province, D. W.; Kahle, K. T.; Weston, M. C.; Barry, J. M.; Luikart, B. W.

As neurons grow, they must regulate intrinsic excitability to maintain an appropriate level of spiking based on synaptic inputs. Using gene knockouts, phosphoproteomics, and electrophysiology we show PTEN regulates neuronal growth and intrinsic excitability through separable downstream mechanisms. Pten loss induces cellular hypertrophy, increased excitatory synaptic input, reduced fast afterhyperpolarization, and burst firing. Deleting the mTORC1 scaffold, Raptor, rescues overgrowth and synaptic input but fails to normalize firing, while deleting Akt or the mTORC2 scaffold, Rictor, restores firing without rescuing growth. This dissociation identifies an AKT-mTORC2 mechanism that regulates voltage-gated calcium and BK potassium channels to set spike repolarization and burst firing. In vivo, Pten knockout produces altered network synchrony, lethal seizures, and impaired object and location behavior; Raptor co-deletion display non-lethal hyperexcitability with improved object-location coupling. The biological and pathophysiological significance of these mechanisms is demonstrated by overlap of the PTEN-regulated phosphoproteome with ASD and epilepsy.