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In a phenotype-driven mutagenesis screen, a novel, dominant mouse mutation,  Nmf350 , caused low seizure threshold, sporadic tonic–clonic seizures, brain enlargement and ectopic neurons in the dentate hilus and molecular layer of the hippocampus. Genetic mapping implicated  Akt3 , one of four candidates within the critical interval. Sequencing analysis revealed that mutants have a missense mutation in  Akt3  (encoding one of three AKT/protein kinase B molecules), leading to a non-synonymous amino acid substitution in the highly conserved protein kinase domain. Previous knockout studies showed that  Akt3  is pivotal in postnatal brain development, including a smaller brain, although seizures were not observed. In contrast to  Akt3 Nmf350  , we find that  Akt3  null mice exhibit an elevated seizure threshold. An  in vitro  kinase assay revealed that  Akt3 Nmf350   confers higher enzymatic activity, suggesting that  Akt3 Nmf350   might enhance AKT signaling in the brain. In the dentate gyrus of  Akt3 Nmf350   homozygotes, we also observed a modest increase in immunoreactivity of phosphorylated ribosomal protein S6, an AKT pathway downstream target. Together these findings suggest that  Akt3 Nmf350   confers an increase of AKT3 activity in specific neuronal populations in the brain, and a unique dominant phenotype.  Akt3 Nmf350   mice provide a new tool for studying physiological roles of AKT signaling in the brain, and potentially novel mechanisms for epilepsy.

A novel Akt3 mutation associated with enhanced kinase activity and seizure susceptibility in mice