Elsevier

Neurobiology of Aging

Volume 18, Issue 4, July–August 1997, Pages 445-452
Neurobiology of Aging

Articles
Age-Related Decrease in the N-Methyl-d-AspartateR-Mediated Excitatory Postsynaptic Potential in Hippocampal Region CA1

https://doi.org/10.1016/S0197-4580(97)00044-4Get rights and content

Abstract

Glutamatergic fast synaptic transmission is known to be altered with age in a region-specific manner in hippocampus of memory-impaired old rats. In the present experiment, presynaptic fiber potentials and non-N-methyl-d-aspartate (NMDAR) and NMDAR-mediated synaptic responses in CA1 were compared in three ages of behaviorally characterized male F-344 rats. In the CA1 region, old rats showed approximately equivalent reductions in non-NMDAR- and NMDAR-excitatory postsynaptic potential amplitudes for a given size of presynaptic fiber potential. There was no change in magnitude of the presynaptic response itself at any stimulus level. These results are consistent with the hypothesis that there is a reduction in the number of Schaffer collateral synapses per presynaptic axon. This pattern of results in CA1 is very different from what is known to occur at the perforant path—granule cell synapse. In fascia dentata the non-NMDAR-mediated excitatory postsynaptic potential is increased in amplitude, although the NMDAR-mediated excitatory postsynaptic potential is reduced for a given presynaptic input. These data suggest that age-related functional alterations in neurotransmitter receptor subtypes occur differentially between closely-related anatomical subregions.

Section snippets

Method

Three age groups of F-344 male rats (n = 10, 1 month; 10, 9 months; 14, 26 months) were behaviorally tested between 3–14 days before the conduct of the electrophysiological experiments. The 1-month rats were obtained from Charles River Laboratories (Wilmington, MA), and the 9- and 26-month rats were retired breeders obtained from the National Institute on Aging (NIA) colony at Harlan Sprague-Dawley, Indianapolis, IN. On arrival, the rats were singly housed in Plexiglas guinea pig tubs with free

Acquisition and retention of the spatial version of the Morris swim task.

Four old animals exhibited severe impairment on the visible platform task (latency to the visible platform >20 s), due to thigmotaxis, apparent inability to see the platform, or inability to swim. These rats were excluded from the behavioral and electrophysiological analyses. Data from the spatial and cued versions of the Morris swim task were analyzed for 10 animals in each age group.

The total distance of the path taken between release in the pool and escape onto the hidden platform, for each

Discussion

The principal new finding of our experiment is the observation of an equivalent age-related decline in the NMDAR and non-NMDAR-mediated EPSPs for a given fiber potential amplitude in CA1. This finding is consistent with the conclusion that, during aging, there is a reduction in the number of Schaffer collateral synapses, with no change in either the relative or absolute amplitudes of NMDAR- or non-NMDAR-mediated synaptic responses at individual remaining synapses. If there are, in fact, fewer

Acknowledgements

We thank B. L. McNaughton for helpful discussions in the planning stages of this work, and constructive suggestions for the preparation of these data for publication.

References (59)

  • T.C. Foster et al.

    Increase in perforant path quantal size in aged F-344 rats

    Neurobiol. Aging

    (1991)
  • Y. Geinisman et al.

    Hippocampal markers of age-related memory dysfunctionbehavioral, electrophysiological and morphological perspectives

    Prog. Neurobiol.

    (1995)
  • R.A. Gonzales et al.

    N-methyl-d-aspartate mediated responses decrease with age in Fischer 344 rat brain

    Neurobiol. Aging

    (1991)
  • J.T. Greenamyre et al.

    Excitatory amino acids and Alzheimer’s disease

    Neurobiol. Aging

    (1989)
  • H. Haas et al.

    A simple perfusion chamber for the study of nervous tissue slices in vitro

    J. Neurosci. Methods

    (1979)
  • C.E. Herron et al.

    A selective N-methyl-d-aspartate antagonist depresses epileptiform activity in rat hippocampal slices

    Neurosci. Lett.

    (1985)
  • S. Hestrin et al.

    Mechanisms generating the time course of dual component excitatory synaptic currents recorded in hippocampal slices

    Neuron

    (1990)
  • D.K. Ingram et al.

    Reduced density of NMDA receptors and increased sensitivity to dizocilpine-induced learning impairment in aged rats

    Brain Res.

    (1992)
  • R.D. Kusztos et al.

    Effects of aging and chronic nimodipine on hippocampal binding of [3H]CGS 19755

    Neurobiol. Aging

    (1996)
  • P.W. Landfield et al.

    Impaired synaptic potentiation process in the hippocampus of aged, memory deficient rats

    Brain Res.

    (1978)
  • M.D. Lindner et al.

    Relationship between performance in the Morris water task, visual acuity, and thermoregulatory function in aged Fischer-344 rats

    Behav. Brain Res.

    (1991)
  • B.L. McNaughton et al.

    Synaptic enhancement in fascia dentatacooperativity among coactive afferents

    Brain Res.

    (1978)
  • R.S. Neuman et al.

    Blockade of excitatory synaptic transmission by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) in the hippocampus in vitro

    Neurosci. Lett.

    (1988)
  • A. Pittaluga et al.

    Age-related decreases of the NMDA receptor-mediated noradrenaline release in rat hippocampus and partial restoration by d-cycloserine

    Euro. J. Pharmacol.

    (1993)
  • G. Rao et al.

    Effects of age on l-glutamate-induced depolarization in three hippocampal subfields

    Neurobiol. Aging

    (1993)
  • J. Shen et al.

    Age-related decrease in cholinergic synaptic transmission in three hippocampal subfields

    Neurobiol. Aging

    (1996)
  • T.R. Shew et al.

    Presynaptic actions of glutamate receptor agonists in the CA1 region of rat hippocampus in vitro

    Eur. J. Pharmacol.

    (1995)
  • M. Tamaru et al.

    Age-related decreases of the N-methyl-D-aspartate receptor complex in the rat cerebral cortex and hippocampus

    Brain Res.

    (1991)
  • G.L. Wenk et al.

    Loss of NMDA, but not GABA-A, binding in the brains of aged rats and monkeys

    Neurobiol. Aging

    (1991)
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