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Brain-specific suppression of AMPKα2 isoform impairs cognition and hippocampal LTP by PERK-mediated eIF2α phosphorylation

Molecular Psychiatry volume 26, pages 1880–1897 (2021)Cite this article

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Abstract

The AMP-activated protein kinase (AMPK) is a molecular sensor to maintain energy homeostasis. The two isoforms of the AMPK catalytic subunit (AMPKα1 and α2) are both expressed in brains, but their roles in cognition are unknown. We generated conditional knockout mice in which brain AMPKα isoforms are selectively suppressed (AMPKα1/α2 cKO), and determined the isoform-specific effects in mice of either sex on cognition and synaptic plasticity. AMPKα2 cKO but not AMPKα1 cKO displayed impaired cognition and hippocampal late long-term potentiation (L-LTP). Further, AMPKα2 cKO mice exhibited decreased dendritic spine density and abnormal spine morphology in hippocampus. Electron microscope imaging demonstrated reduced postsynaptic density formation and fewer dendritic polyribosomes in hippocampi of AMPKα2 cKO mice. Biochemical studies revealed unexpected findings that repression of AMPKα2 resulted in increased phosphorylation of mRNA translational factor eIF2α and its kinase PERK. Importantly, L-LTP failure and cognitive impairments displayed in AMPKα2 cKO mice were alleviated by suppressing PERK activity pharmacologically or genetically. In summary, we demonstrate here that brain-specific suppression of AMPKα2 isoform impairs cognition and hippocampal LTP by PERK-mediated eIF2α phosphorylation, providing molecular mechanisms linking metabolism, protein synthesis, and cognition.

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Fig. 1: Characterization of Forebrain- and Isoform-specific AMPKα knockout mice.
Fig. 2: Learning and memory are impaired in AMPKα2 cKO mice but unaffected in AMPKα1 cKO mice.
Fig. 3: Hippocampal L-LTP is impaired in AMPKα2 cKO mice but unaltered in AMPKα1 cKO mice.
Fig. 4: AMPKα2 cKO mice display abnormal hippocampal dendritic spine morphology and impaired postsynaptic density formation.
Fig. 5: Isoform-specific regulation of protein synthesis in AMPKα cKO mice.
Fig. 6: Increased phosphorylation of eIF2α and PERK in AMPKα2 cKO mice.
Fig. 7: Suppression of PERK activity alleviates L-LTP failure and cognitive impairments in AMPKα2 cKO mice.

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Acknowledgements

We thank Dr Eric Klann of the New York University for providing the original breeders for the PERK cKO mice. We thank Mr Kenneth Grant for technical help on EM imaging. We thank Karen Klein, MA, in the Wake Forest Clinical and Translational Science Institute (UL1 TR001420) for editing the manuscript. This work was supported by National Institutes of Health grants K99/R00 AG044469, R01 AG055581, R01 AG056622 (TM), F31AG055264 (HRZ), the Alzheimer’s Association grant NIRG-15-362799 (TM), the BrightFocus Foundation grant A2017457S (TM), Wake Forest Alzheimer’s Disease Core Center (ADCC) pilot grant (TM), and a Wake Forest Clinical and Translational Science Institute (CTSI) pilot grant (TM). The mass spectrometry analysis was performed by the Proteomics and Metabolomics Shared Resource at Wake Forest School of Medicine, which is partly supported by the Comprehensive Cancer Support Grant (P30CA012197).

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  1. These authors contributed equally: Wenzhong Yang, Xueyan Zhou

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  1. Department of Internal Medicine-Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA

    Wenzhong Yang, Xueyan Zhou, Helena R. Zimmermann & Tao Ma

  2. Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA

    Tao Ma

  3. Department of Neurobiology and Anatomy, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA

    Tao Ma

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Yang, W., Zhou, X., Zimmermann, H.R. et al. Brain-specific suppression of AMPKα2 isoform impairs cognition and hippocampal LTP by PERK-mediated eIF2α phosphorylation. Mol Psychiatry 26, 1880–1897 (2021). https://doi.org/10.1038/s41380-020-0739-z

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