Age-related working memory impairment is correlated with increases in the L-type calcium channel protein alpha1D (Cav1.3) in area CA1 of the hippocampus and both are ameliorated by chronic nimodipine treatment

Brain Res Mol Brain Res. 2003 Feb 20;110(2):193-202. doi: 10.1016/s0169-328x(02)00643-5.

Abstract

The hippocampus is critical for spatial memory formation in rodents. Calcium currents through L-type voltage-sensitive calcium channels (L-VSCCs) are increased in CA1 neurons of the hippocampus of aged rats. We have recently shown that expression of the calcium conducting L-VSCC subunit alpha(1D) (Ca(v)1.3) is selectively increased in area CA1 of aged rats. We and others have speculated that excessive Ca(2+) influx through L-VSCC may be detrimental to memory formation. Therefore, we investigated the relationship between age-related working memory decline and alpha(1D) protein expression in the hippocampus. In addition, we studied the effects of chronic treatment with the L-VSCC antagonist nimodipine (NIM) on age-related working memory deficits and alpha(1D) expression in the hippocampus. Here we report that age-related increases in alpha(1D) expression in area CA1 correlate with working memory impairment in Fischer 344 rats. Furthermore, we demonstrate that chronic NIM treatment ameliorates age-related working memory deficits and reduces expression of alpha(1D) protein in the hippocampus. The present results suggest that L-VSCCs participate in processes underlying memory formation and that increases in L-VSCC protein and currents observed with aging may play a role in age-related memory decline. Furthermore, the amelioration in age-related memory decline produced by NIM treatment may be mediated, at least in part, by reductions in the abnormally high levels of alpha(1D) protein in the aged hippocampus. These findings may have implications for patients with Alzheimer's disease, who show increased L-VSCC protein expression in the hippocampus, and for patients receiving chronic treatment with L-VSCC antagonists.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aging / metabolism*
  • Animals
  • Calcium Channel Blockers / pharmacology*
  • Calcium Channels
  • Calcium Channels, L-Type / drug effects
  • Calcium Channels, L-Type / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Hippocampus / drug effects
  • Hippocampus / metabolism*
  • Hippocampus / physiopathology
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Memory Disorders / drug therapy
  • Memory Disorders / metabolism*
  • Memory Disorders / physiopathology
  • Neurons / drug effects
  • Neurons / metabolism
  • Nimodipine / pharmacology*
  • Rats
  • Rats, Inbred F344
  • Reaction Time / drug effects
  • Reaction Time / physiology
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Synapses / drug effects
  • Synapses / metabolism
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology

Substances

  • Calcium Channel Blockers
  • Calcium Channels
  • Calcium Channels, L-Type
  • NR2A NMDA receptor
  • NR2B NMDA receptor
  • Receptors, N-Methyl-D-Aspartate
  • Cacna1d protein, rat
  • Nimodipine
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases