The 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.
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We would like to thank Dr. Daniel Weinberger of the Lieber Institute for Brain Development and previously the NIMH Intramural Research Program, for additional resource support at the NIMH IRP. We thank Dr. Wenwei Huang, Dr. Craig Thomas and the National Center for Advancing Translational Sciences, National Institutes of Health for the synthesis of the IC87114 compound. All the work presented in this study was conducted at the NIMH Intramural Research Program, Bethesda, MD and the University of Colorado, CO, USA.
This work was supported by the National Institutes of Mental Health under Award Number R01MH103716 (AJL), http://grantome.com/grant/NIH/R01-MH103716-05 and previously by funds from the National Institutes of Mental Health, Intramural Research Program (AJL). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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Palumbo, S., Paterson, C., Yang, F. et al. PKBβ/AKT2 deficiency impacts brain mTOR signaling, prefrontal cortical physiology, hippocampal plasticity and select murine behaviors. Mol Psychiatry 26, 411–428 (2021). https://doi.org/10.1038/s41380-020-00964-4
Signal Transduction and Targeted Therapy (2021)