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. 2019 Feb 4;29(3):435-448.e8.
doi: 10.1016/j.cub.2018.12.021. Epub 2019 Jan 17.

Autophagy Is Required for Memory Formation and Reverses Age-Related Memory Decline

Mélissa Glatigny  1 , Stéphanie Moriceau  1 , Manon Rivagorda  1 , Mariana Ramos-Brossier  1 , Anna C Nascimbeni  2 , Fabien Lante  3 , Mary R Shanley  4 , Nadir Boudarene  1 , Audrey Rousseaud  1 , Allyson K Friedman  4 , Carmine Settembre  5 , Nicolas Kuperwasser  6 , Gérard Friedlander  2 , Alain Buisson  3 , Etienne Morel  2 , Patrice Codogno  7 , Franck Oury  8
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Free article

Autophagy Is Required for Memory Formation and Reverses Age-Related Memory Decline

Mélissa Glatigny et al. Curr Biol. .
Free article

Abstract

Age-related declines in cognitive fitness are associated with a reduction in autophagy, an intracellular lysosomal catabolic process that regulates protein homeostasis and organelle turnover. However, the functional significance of autophagy in regulating cognitive function and its decline during aging remains largely elusive. Here, we show that stimulating memory upregulates autophagy in the hippocampus. Using hippocampal injections of genetic and pharmacological modulators of autophagy, we find that inducing autophagy in hippocampal neurons is required to form novel memory by promoting activity-dependent structural and functional synaptic plasticity, including dendritic spine formation, neuronal facilitation, and long-term potentiation. We show that hippocampal autophagy activity is reduced during aging and that restoring its levels is sufficient to reverse age-related memory deficits. Moreover, we demonstrate that systemic administration of young plasma into aged mice rejuvenates memory in an autophagy-dependent manner, suggesting a prominent role for autophagy to favor the communication between systemic factors and neurons in fostering cognition. Among these youthful factors, we identify osteocalcin, a bone-derived molecule, as a direct hormonal inducer of hippocampal autophagy. Our results reveal that inducing autophagy in hippocampal neurons is a necessary mechanism to enhance the integration of novel stimulations of memory and to promote the influence of systemic factors on cognitive fitness. We also demonstrate the potential therapeutic benefits of modulating autophagy in the aged brain to counteract age-related cognitive impairments.

Keywords: aging; autophagy; beclin 1; hippocampus; memory formation; osteocalcin; synaptic plasticity; systemic milieu; youthful circulating factors.

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  • Autophagy Promotes Memory Formation.
    Tripathi T, Kalita P, Martins R, Bharadwaj P. Tripathi T, et al. ACS Chem Neurosci. 2019 Aug 21;10(8):3337-3339. doi: 10.1021/acschemneuro.9b00317. Epub 2019 Jun 18. ACS Chem Neurosci. 2019. PMID: 31244056

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