Elevated Postsynaptic [Ca2+]i and L-type Calcium Channel Activity in Aged Hippocampal Neurons: Relationship to Impaired Synaptic Plasticity

J Neurosci. 2001 Dec 15;21(24):9744-56. doi: 10.1523/JNEUROSCI.21-24-09744.2001.

Abstract

Considerable evidence supports a Ca(2+) dysregulation hypothesis of brain aging and Alzheimer's disease. However, it is still not known whether (1) intracellular [Ca(2+)](i) is altered in aged brain neurons during synaptically activated neuronal activity; (2) altered [Ca(2+)](i) is directly correlated with impaired neuronal plasticity; or (3) the previously observed age-related increase in L-type voltage-sensitive Ca(2+) channel (L-VSCC) density in hippocampal neurons is sufficient to impair synaptic plasticity. Here, we used confocal microscopy to image [Ca(2+)](i) in single CA1 neurons in hippocampal slices of young-adult and aged rats during repetitive synaptic activation. Simultaneously, we recorded intracellular EPSP frequency facilitation (FF), a form of short-term synaptic plasticity that is impaired with aging and inversely correlated with cognitive function. Resting [Ca(2+)](i) did not differ clearly with age. Greater elevation of somatic [Ca(2+)](i) and greater depression of FF developed in aged neurons during 20 sec trains of 7 Hz synaptic activation, but only if the activation triggered repetitive action potentials for several seconds. Elevated [Ca(2+)](i) and FF also were negatively correlated in individual aged neurons. In addition, the selective L-VSCC agonist Bay K8644 increased the afterhyperpolarization and mimicked the depressive effects of aging on FF in young-adult neurons. Thus, during physiologically relevant firing patterns in aging neurons, postsynaptic Ca(2+) elevation is closely associated with altered neuronal plasticity. Moreover, selectively increasing postsynaptic L-VSCC activity, as occurs in aging, negatively regulated a form of short-term plasticity that enhances synaptic throughput. Together, the results elucidate novel processes that may contribute to impaired cognitive function in aging.

Publication types

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

MeSH terms

  • 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / pharmacology
  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Aging / metabolism*
  • Animals
  • Calcium / metabolism*
  • Calcium Channel Agonists / pharmacology
  • Calcium Channels, L-Type / metabolism*
  • Dendrites / ultrastructure
  • Electric Stimulation / methods
  • Excitatory Postsynaptic Potentials / physiology
  • Fluorescent Dyes
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • In Vitro Techniques
  • Intracellular Fluid / metabolism
  • Male
  • Microscopy, Confocal
  • Neuronal Plasticity / physiology*
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • Patch-Clamp Techniques
  • Rats
  • Rats, Inbred F344
  • Synapses / metabolism*

Substances

  • Calcium Channel Agonists
  • Calcium Channels, L-Type
  • Fluorescent Dyes
  • 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
  • Calcium