PKBβ/AKT2 deficiency impacts brain mTOR signaling, prefrontal cortical physiology, hippocampal plasticity and select murine behaviors

he serine/threonine protein kinase v-AKT homologs (AKTs), are implicated in typical and atypical neurodevelopment. Akt isoforms Akt1, Akt2, and Akt3 have been extensively studied outside the brain where their actions have been found to be complementary, non-overlapping and often divergent. While the neurological functions of Akt1 and Akt3 isoforms have been investigated, the role for Akt2 remains underinvestigated. Neurobehavioral, electrophysiological, morphological and biochemical assessment of Akt2 heterozygous and knockout genetic deletion in mouse, reveals a novel role for Akt2 in axonal development, dendritic patterning and cell-intrinsic and neural circuit physiology of the hippocampus and prefrontal cortex. Akt2 loss-of-function increased anxiety-like phenotypes, impaired fear conditioned learning, social behaviors and discrimination memory. Reduced sensitivity to amphetamine was observed, supporting a role for Akt2 in regulating dopaminergic tone. Biochemical analyses revealed dysregulated brain mTOR and GSK3β signaling, consistent with observed learning and memory impairments. Rescue of cognitive impairments was achieved through pharmacological enhancement of PI3K/AKT signaling and PIK3CD inhibition. Together these data highlight a novel role for Akt2 in neurodevelopment, learning and memory and show that Akt2 is a critical and non-redundant regulator of mTOR activity in brain.