Increased learning and brain long-term potentiation in aged mice lacking DNA polymerase μ

PLoS One. 2013;8(1):e53243. doi: 10.1371/journal.pone.0053243. Epub 2013 Jan 3.

Abstract

A definitive consequence of the aging process is the progressive deterioration of higher cognitive functions. Defects in DNA repair mechanisms mostly result in accelerated aging and reduced brain function. DNA polymerase µ is a novel accessory partner for the non-homologous end-joining DNA repair pathway for double-strand breaks, and its deficiency causes reduced DNA repair. Using associative learning and long-term potentiation experiments, we demonstrate that Polµ(-/-) mice, however, maintain the ability to learn at ages when wild-type mice do not. Expression and biochemical analyses suggest that brain aging is delayed in Polµ(-/-) mice, being associated with a reduced error-prone DNA oxidative repair activity and a more efficient mitochondrial function. This is the first example in which the genetic ablation of a DNA-repair function results in a substantially better maintenance of learning abilities, together with fewer signs of brain aging, in old mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging*
  • Animals
  • Behavior, Animal
  • Brain / metabolism
  • Brain / physiology*
  • Conditioning, Classical
  • DNA / genetics
  • DNA Repair
  • DNA-Directed DNA Polymerase / genetics
  • DNA-Directed DNA Polymerase / metabolism*
  • Hippocampus / metabolism
  • Learning*
  • Locomotion
  • Long-Term Potentiation / genetics*
  • Male
  • Mice
  • Mice, Knockout
  • Oxidative Stress
  • Phenotype
  • Reproducibility of Results
  • Temperature

Substances

  • DNA
  • DNA polymerase mu
  • DNA-Directed DNA Polymerase

Grant support

This work was supported by grants BFU2008-03390/BMC/MICINN (A.G.), BFU2008-00899/MICINN (J.M.D.-G.), BFU2007-60263/MICINN and PAC08-0261-1581/JCCM (A.F.), and SAF 2008-02099/MICINN and PLE2009-0147 (A.B.) from the Spanish Ministry of Education and Reserach. D.L. was a fellow of the Spanish Fundación Ramón Areces. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.