LKB1 and AMPK regulate synaptic remodeling in old age

Nat Neurosci. 2014 Sep;17(9):1190-7. doi: 10.1038/nn.3772. Epub 2014 Aug 3.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics*
  • AMP-Activated Protein Kinases / metabolism
  • Aging / pathology
  • Aging / physiology*
  • Amacrine Cells / pathology
  • Amacrine Cells / physiology
  • Animals
  • Electroretinography
  • Female
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphorylation / physiology
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Retinal Bipolar Cells / pathology
  • Retinal Bipolar Cells / physiology
  • Retinal Ganglion Cells / pathology
  • Retinal Ganglion Cells / physiology
  • Rod Cell Outer Segment / pathology*
  • Rod Cell Outer Segment / physiology*
  • Substrate Specificity
  • Synapses / pathology
  • Synapses / physiology

Substances

  • Stk11 protein, mouse
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases