Team Evans and Watkins: Excitatory Amino Acid research at Bristol University 1973-1981.

A series of Special Issues of Neuropharmacology celebrates the 40th anniversary of a seminal review on excitatory amino acid (EAA) receptors by two pioneers of the field - Dick Evans and Jeff Watkins. Brought together in the Department of Pharmacology at the University of Bristol in the 1970s, they forged a partnership that, through the synthetic chemistry prowess of Jeff Watkins, which provided novel agonists and antagonists for EAA receptors for Dick Evans's deft experimental studies, generated enormous insight into the multitude of actions of EAAs in the nervous system. Among many achievements from this time was not just the naming of the N-methyl-d-aspartate (NMDA) receptor, but also the demonstration of its antagonism by magnesium ions. Here, Dick and Jeff reflect upon those early halcyon days of EAA research, which, as these six1 Special Issues of Neuropharmacology demonstrate, is very much alive and kicking. Bruno G. Frenguelli, Editor-in-Chief, Neuropharmacology.

Ionotropic glutamate receptor biology: effect on synaptic connectivity and function in neurological disease.

Glutamate receptor signaling is essential to normal synaptic function in the central nervous system. The major ionotropic glutamate receptors (AMPA, Kainic, and NMDA) have different synaptic functions depending upon cellular and subcellular localization, subunit composition, and second messenger systems linked to the receptors. In this review, we examine major advances in glutamate receptor biology whose physiology plays a central role in neurologic disease such as epilepsy and stroke. A key feature of glutamate receptor activation in neurologic disease is the downstream effects on cell survival, genetic expression of axon guidance cues, synaptic connectivity/formation of networks, and neuronal excitability. Identification of therapeutic pharmacologic targets and development of antagonists specific to the disease process remain central themes in epilepsy and stroke research.

The dawn of excitatory amino acid research in Japan. The pioneering work by Professor Takashi Hayashi.

The excitatory action of glutamate and aspartate upon direct application to the motor cortex of dogs was first reported in 1952 by Takashi Hayashi, Keio University School of Medicine, Tokyo. Although this investigation had been performed in the early 1940s during the Second World War, the publication in English was delayed in the difficult post-war circumstances. When sodium glutamate was applied to the exposed motor cortex in 1-2 mol (not mmol) concentrations, the convulsions of a clonic type were produced with very short latent periods. He injected glutamate free-hand by using an intradermic syringe for humans. Stimulation by glutamate was solely effective in the grey matter. If entered into the white matter, it had no motor effects. When Hayashi undertook this investigation, glutamate was not known to exist in a high concentration in the brain. Hayashi proposed the physiological role of glutamate in the brain excitation, and hypothesized that glutamate might be inactive in the brain tissue, probably bound to protein, and that upon release from protein the excitatory action might be expressed. The electrical stimulation of the cortex was suggested to induce the release of glutamate from protein.