Cited by 114Retinal Development and DisordersNeuroscience and Neuropharmacology ResearchGenetics, Aging, and Longevity in Model Organisms

LKB1 and AMPK regulate synaptic remodeling in old age

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Samuel, Melanie A, Voinescu, P Emanuela, Lilley, Brendan N, de Cabo, Rafa, Foretz, Marc, Viollet, Benoit, Pawlyk, Basil, Sandberg, Michael A +2 more·2014·Nature Neuroscience

Abstract

Age-related decreases in neural function result in part from alterations in synapses. To identify molecular defects that lead to such changes, we focused on the outer retina, in which synapses are markedly altered in old rodents and humans. We found that the serine/threonine kinase LKB1 and one of its substrates, AMPK, regulate this process. In old mice, synaptic remodeling was accompanied by specific decreases in the levels of total LKB1 and active (phosphorylated) AMPK. In the absence of either kinase, young adult mice developed retinal defects similar to those that occurred in old wild-type animals. LKB1 and AMPK function in rod photoreceptors where their loss leads to aberrant axonal retraction, the extension of postsynaptic dendrites and the formation of ectopic synapses. Conversely, increasing AMPK activity genetically or pharmacologically attenuates and may reverse age-related synaptic alterations. Together, these results identify molecular determinants of age-related synaptic remodeling and suggest strategies for attenuating these changes.

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Authors
Samuel, M. A., Voinescu, P. E., Lilley, B. N., de Cabo, R., Foretz, M., Viollet, B., Pawlyk, B., Sandberg, M. A., Vavvas, D. G., & Sanes, J. R.
Affiliations
  • Harvard University (US)
  • Centre National de la Recherche Scientifique (FR)
  • Massachusetts Eye and Ear Infirmary (US)
Corresponding author
Sanes, Joshua R
Venue
Nature Neuroscience
Published
2014-08-03
Volume
17
Issue
9
Pages
1190-1197
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
OpenAlex
W2005226793
Cited by
114
References
62
Citations by year
2026: 3 · 2025: 7 · 2024: 8 · 2023: 9 · 2022: 10 · 2021: 14 · 2020: 16 · 2019: 8 · 2018: 14 · 2017: 6 · 2016: 8 · 2015: 8 · 2014: 2 · 2013: 1
FWCI
3.28
Type
journal article
Language
en
Open access
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (AG32322, R01AG032322, K99AG044444)
  • National Eye Institute (R21EY023079)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
LKB1, AMPK, synaptic remodeling, aging, caloric restriction, metformin, rod photoreceptors, axonal retraction, age-related retinal degeneration, kinase signaling
MeSH terms
Aging, Animals, Electroretinography, Female, Male, Mice, Inbred C57BL, Phosphorylation, Retinal Ganglion Cells, Rod Cell Outer Segment, Substrate Specificity, Synapses, Protein Serine-Threonine Kinases, Mice, Knockout, Amacrine Cells, Retinal Bipolar Cells, AMP-Activated Protein Kinases

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