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

Abstract

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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Fig. 1: Akt2 HET and KO mice show altered locomotor activity, response to amphetamine, associative learning of environmental context, and reassessment of a learned aversive cue.
Fig. 2: Akt2 genetically modified mice display impaired recency discrimination memory and object location memory, but intact novel object memory.
Fig. 3: Abnormal sociability and social novelty preference in Akt2 HET and KO mice.
Fig. 4: Significant impairment of hippocampal LTP and decreased mPFC pyramidal neuron excitability in Akt2 KO mice.
Fig. 5: Preclinical relevance of PIK3CD signaling and pharmacological inhibition in Akt2 mice and evidence that Akt2 regulates mTOR signaling.

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Acknowledgements

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.

Funding

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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SP and CP performed experiments, performed data analysis and authored manuscript text; FY performed electrophysiology experiments, performed data analysis and revised manuscript drafts; VLH performed cell culture experiments and performed data analysis; AJL conceived and designed the study, performed data analysis, statistical analysis, authored manuscript text, revised manuscript drafts, and supervised this work.

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Correspondence to Amanda J. Law.

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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

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