Treatment strategies targeting excess hippocampal activity benefit aged rats with cognitive impairment

Neuropsychopharmacology. 2010 Mar;35(4):1016-25. doi: 10.1038/npp.2009.207. Epub 2009 Dec 23.


Excess neural activity in the CA3 region of the hippocampus has been linked to memory impairment in aged rats. We tested whether interventions aimed at reducing this excess activity would improve memory performance. Aged (24 to 28 months old) male Long-Evans rats were characterized in a spatial memory task known to depend on the functional integrity of the hippocampus, such that aged rats with identified memory impairment were used in a series of experiments. Overexpression of the inhibitory neuropeptide Y 13-36 in the CA3 via adeno-associated viral transduction was found to improve hippocampal-dependent long-term memory in aged rats, which had been characterized with impairment. Subsequent experiments with two commonly used antiepileptic agents, sodium valproate and levetiracetam, similarly produced dose-dependent memory improvement in such aged rats. Improved spatial memory with low doses of these agents was observed in both appetitve and aversive spatial tasks. The benefits of these different modalities of treatment are consistent with the concept that excess activity in the CA3 region of the hippocampus is a dysfunctional condition that may have a key role underlying age-related impairment in hippocampal-dependent memory processes. Because increased hippocampal activation occurs in age-related memory impairment in humans as observed in functional neuroimaging, the current findings also suggest that low doses of certain antiepileptic drugs in cognitively impaired elderly humans may have therapeutic potential and point to novel targets for this indication.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Age Factors
  • Aging*
  • Animals
  • Anticonvulsants / therapeutic use
  • CA3 Region, Hippocampal / drug effects
  • CA3 Region, Hippocampal / physiology*
  • Cognition Disorders / drug therapy
  • Cognition Disorders / pathology*
  • Cognition Disorders / physiopathology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Levetiracetam
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Neuropeptide Y / administration & dosage
  • Neuropeptide Y / pharmacology
  • Peptide Fragments / administration & dosage
  • Peptide Fragments / pharmacology
  • Piracetam / analogs & derivatives
  • Piracetam / therapeutic use
  • Rats
  • Rats, Long-Evans
  • Space Perception / drug effects
  • Space Perception / physiology
  • Transduction, Genetic / methods
  • Valproic Acid / therapeutic use


  • Anticonvulsants
  • Drug Combinations
  • Neuropeptide Y
  • Peptide Fragments
  • neuropeptide Y (13-36)
  • Levetiracetam
  • Valproic Acid
  • Piracetam