title: A novel Akt3 mutation associated with enhanced kinase activity and seizure susceptibility in mice.
abstract: 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.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Satoko
authors.initials: S
authors.lastname: Tokuda
authors.forename: Connie L
authors.initials: CL
authors.lastname: Mahaffey
authors.forename: Bobby
authors.initials: B
authors.lastname: Monks
authors.forename: Christian R
authors.initials: CR
authors.lastname: Faulkner
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Birnbaum
authors.forename: Steve C
authors.initials: SC
authors.lastname: Danzer
authors.forename: Wayne N
authors.initials: WN
authors.lastname: Frankel
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004198:Disease Susceptibility; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000201:enzymology* / Q000235:genetics; D016415:Sequence Alignment; D015398:Signal Transduction
chemical_list: C491753:Akt3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases