Low hippocampal PI(4,5)P₂ contributes to reduced cognition in old mice as a result of loss of MARCKS

Nat Neurosci. 2013 Apr;16(4):449-55. doi: 10.1038/nn.3342. Epub 2013 Feb 24.


Cognitive and motor performances decline during aging. Although it is clear that such signs reflect synaptic compromise, the underlying mechanisms have not been defined. We found that the levels and activity of the synaptic plasticity modulators phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P₂) and phospholipase Cγ (PLCγ) were substantially reduced in hippocampal synaptic membranes from old mice. In addition, these membranes contained reduced levels of the PI(4,5)P₂-clustering molecule myristoylated alanine-rich C kinase substrate (MARCKS). Consistent with a cause-effect relationship, raising MARCKS levels in the brain of old mice led to increased synaptic membrane clustering of PI(4,5)P₂ and to PLCγ activation. MARCKS overexpression in the hippocampus of old mice or intraventricular perfusion of MARCKS peptide resulted in enhanced long-term potentiation and improved memory. These results reveal one of the mechanisms involved in brain dysfunction during aging.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / drug effects
  • Aging / physiology*
  • Animals
  • Cells, Cultured
  • Cognition Disorders / drug therapy
  • Cognition Disorders / physiopathology*
  • Down-Regulation / physiology*
  • Hippocampus / drug effects
  • Hippocampus / physiology*
  • Infusions, Intraventricular
  • Intracellular Signaling Peptides and Proteins / administration & dosage
  • Intracellular Signaling Peptides and Proteins / deficiency*
  • Male
  • Membrane Proteins / administration & dosage
  • Membrane Proteins / deficiency*
  • Mice
  • Mice, Inbred C57BL
  • Myristoylated Alanine-Rich C Kinase Substrate
  • Neurons / drug effects
  • Neurons / physiology
  • Organ Culture Techniques
  • Phosphatidylinositol 4,5-Diphosphate / physiology*
  • Rats


  • Intracellular Signaling Peptides and Proteins
  • Marcks protein, mouse
  • Marcks protein, rat
  • Membrane Proteins
  • Phosphatidylinositol 4,5-Diphosphate
  • Myristoylated Alanine-Rich C Kinase Substrate