The 1980s: D-AP5, LTP and a Decade of NMDA Receptor Discoveries

Abstract

In the 1960s and 70s, biochemical and pharmacological evidence was pointing toward glutamate as a synaptic transmitter at a number of distinct receptor classes, known as NMDA and non-NMDA receptors. The field, however, lacked a potent and highly selective antagonist to block these putative postsynaptic receptors. So, the discoveries in the early 1980s of D-AP5 as a selective NMDA receptor antagonist and of its ability to block synaptic events and plasticity were a major breakthrough leading to an explosion of knowledge about this receptor subtype. During the next 10 years, the role of NMDA receptors was established in synaptic transmission, long-term potentiation, learning and memory, epilepsy, pain, among others. Hints at pharmacological heterogeneity among NMDA receptors were followed by the cloning of separate subunits. The purpose of this review is to recognize the important contributions made in the 1980s by Graham L. Collingridge and other key scientists to the advances in our understanding of the functions of NMDA receptors throughout the central nervous system.

Keywords: APV; D-AP5; Long-term potentiation (LTP); NMDA; NMDA receptors; Synaptic plasticity.

Fig. 1

d-AP5, NMDA and NMDA receptor-dependent synaptic plasticity in 1983. a Iontophoretic application of d-AP5 blocks induction of LTP, which can be readily induced after washout of the antagonist [1]. b Brief iontophoretic application of NMDA leads to a transient enhancement of field potential amplitude, which declines to baseline over time [1]. c Longer, bath application, of NMDA leads to a permanent depression of synaptic transmission [49]

Fig. 2

Trends in pharmacological sciences: Special Report 1991. Cover page: This supplement was a compilation of the articles published each month during 1990 on the theme: “The Pharmacology of Excitatory Amino Acids” edited by David Lodge, and Graham L. Collingridge with Alison Abbott of Elsevier. The supplement was sponsored by Leslie L. Iversen of Merck & Sharp and Dohme Research Laboratories. The Glutamate Tree of Life is represented in the “Cover design by Nigel Hynes, based on an original idea of David Lodge”

Fig. 3

Pharmacology of excitatory amino acids: 1991 Poster. This accompanying Poster summarised what had been published in the Special Report. Much of what was simplistically sketched in 1991 still holds true today in 2018 with major advances that have been made in many areas. In particular our knowledge about glutamate receptor involvement in disease has shown huge advances together with advances in the molecular biology, crystal structure, genetics and intracellular signalling of glutamate receptors. Absence of metabotropic glutamate receptors on the illustrated glutamatergic terminal and of pharmacological tools for these G-protein coupled receptors are obvious omissions. Two areas of neuropsychiatry, namely schizophrenia and depression, are now widely linked with NMDA receptor function