N‐methyl‐D‐aspartate receptors, synaptic plasticity, and Alzheimer's disease

C. W. Cotman, D. T. Monaghan, J. W. Geddes

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Abstract

The NMDA (N‐methyl‐D‐aspartate) excitatory amino acid receptor mediates a potent excitatory response in many regions of the CNS and plays a key role in excitotoxicity and synaptic plasticity. Results from radioligand‐binding studies indicate that NMDA agonists and antagonists preferentially bind to differing populations of NMDA receptors. The distribution of NMDA receptors as labeled by the agonist L‐[3H]glutamate differs from that obtained with the radiolabeled antagonist [3H]3‐((±2‐carboxypiperazine‐4‐yl)‐propyl‐1‐phosphonic acid ([3H]CPP)). In addition, NMDA agonists and antagonists display complementary regional variations in their ability to displace L‐[3H]glutamate binding. At least some of the differences between agonist and antagonist‐binding properties can be accounted for by suggesting that glycine converts the NMDA receptor from an antagonist‐preferring state into an agonist‐preferring state. Since NMDA and other excitatory amino acid receptor functions are necessary for synaptic function, certain forms of synaptic plasticity, and learning, we have evaluated their status in Alzheimer's disease (AD). Using radioligand‐binding techniques, we find that NMDA receptors are generally preserved in the course of AD pathology in the human hippocampus in spite of partial cell loss. Kainate receptors, on the other hand, display a radistribution within the hippocampus. This redistribution corresponds to an apparent synaptic reorganization owing to the loss of input from the entorhinal cortex. The response of both the NMDA and kainate receptor systems may be adaptive plastic responses that attempt to maintain hippocampal function that is compromised by AD. However, these mechanisms may also render the hippocampus more vulnerable to damage following excessive neuronal activation.

Original languageEnglish (US)
Pages (from-to)331-338
Number of pages8
JournalDrug Development Research
Volume17
Issue number4
DOIs
Publication statusPublished - 1989

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Keywords

  • autoradiography
  • glutamate
  • hippocampus
  • kainate receptors

ASJC Scopus subject areas

  • Drug Discovery

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