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John Ferguson MacDonald John Ferguson MacDonald, who died on April 22 in Toronto at the early age of 65, was an outstanding Canadian neuroscientist, whose career was rich in many achievements across a wide variety of research topics, ranging from the mechanisms of action of amino acid transmitters to the role of Ca ions in cerebral stroke. For most of his career, he was a member of the Toronto departments of Pharmacology and Physiology - the latter he headed in 2001-2008. He was then appointed to the Robarts Research Institute, London (Ont) for two years as the Scientific Director; but continued as leader of a very active research group until last year, when he had to retire owing to ill health. John was born in Vancouver. His education there culminated in a PhD in Physiology at UBC (obtained under the supervision of J.A. Pearson). He then spent the next several years greatly broadening his research experience. A giant leap, both in terms of geography and research topic, transported him from his doctoral studies on spinal reflexes in cats to recordings from single neuron in snails, at the Gatty Marine Laboratory, in St Andrews (Scotland). Another leap brought him back to Canada, to my lab at McGill. Clearly, here was highly motivated young researcher, with a thoroughly amiable disposition: low key, but alert, with a pawky sense of humor that reflected his Scottish ancestry. At McGill, he came to work with two other post-docs of very different backgrounds: Andrea Nistri*, originally from Florence, and Yvon Lamour#, from France. Mutually very congenial, they formed a dynamic and productive team. Of the various topics they investigated, two proved of seminal importance for John’s career: amino acids as transmitters, and divalent cations as crucial factors in both normal and abnormal neuronal function. Though he did not stay in Montreal, going on to NIH to continue post-doc studies with Jeffery Barker – mainly on amino acid actions on isolated neurons in cultures – and then returned to Canada to take up a position at the U of T, John’s research had a further major input from Montreal, in the persons of two McGill graduates who were to be important collaborators over several decades: first Michael Salter (PhD in Physiology), notably in a series of experiments demonstrating the crucial role of tyrosine kinases in synaptic plasticity; and later Michael Jackson (PhD in Pharmacology), who joined his group as a post-doc and remained a close collaborator till the end. John MacDonald’s research led to a variety of major advances. One of the first was his discovery that the excitatory action of L-aspartate on spinal neurons – the closest relative of L-glutamate, but now known to bind selectively to NMDA receptors – had an unexpected property: in the presence of Laspartate, current voltage plots revealed a zone of negative conductance, comparable to that seen with fast Na+ currents. The important functional consequence was that the excitatory action of Laspartate was voltage-dependent, increasing with depolarization. These findings (with AV Porietis and JM Wojtowicz) were basic to the recognition of NMDA receptors as a crucial element of synaptic plasticity, thanks to which long term changes in efficacy of transmission provide a cellular mechanism of learning. This pioneering research was followed up by systematic investigations (with M. Salter) of other factors involved in synaptic plasticity, such as phosphorylation-induced selective modulation of glutamate receptors by Src or Fyn tyrosine kinases. His interest in glutamate led John to examine mechanisms related to glutamate’s potentially noxious action: excessive depolarization and Ca2+ influx via NMDARs result in the death of nerve cells, for example following brain ischemia, when large amounts of glutamate are released from neurons and glia. Experiments with Michael Tymianski highlighted the specific role of NMDARs and associated intracellular molecules. Ca2+ influx is not lethal when mediated by other pathways – such as other types of glutamate receptors or voltage-dependent channels. So there was something special about NMDARs. The two key features proved to be, on the one hand, coupling between NMDARs and the internal scaffolding protein (PSD-95), and coupling between PSD-95 and nitric oxide synthase (NOS), on the other – the latter selectively facilitated the activation of NOS by Ca2+ influx via NMDARs and thus the production of neurotoxic nitric oxide. Other experiments focused on ‘transient receptor potential’ (TRP) channels, non-specifically cationpermeable, which can be activated by oxidative stress and changes in extracellular levels of Ca2+. They provide another route for Ca2+ influx, especially that causing the delayed cell death observed after strokes. Together with NMDARs, these channels account for a sequential process of Ca2+ entry, only the early phase of which is susceptible to block by NMDAR antagonists. The group’s findings cast much new light on some puzzling features of brain ischemia – such as the Ca2+ paradox’ (the activation of Ca2+ influx by a drop in extracellular Ca2+) and the disappointing therapeutic effects of NMDA antagonists given to patients. Inhibitory actions of amino acids have also been a major topic of research by his group: for example, the tonic inhibition exerted by extrasynaptic GABA receptors, the marked potentiation of which by several types of general anaesthetics (propofol, isoflurane) is probably an important mechanism of anaesthesia. In the last years, his attention shifted towards amyloid-β plaques formation in Alzheimer’s dementia, and Fyn kinase and prion protein as possible therapeutic targets. A signal feature of John MacDonald’s many publications (some 200 in all) is the clarity of exposition and logic. Though he will be greatly missed, his outstanding ability to train students and form and lead strong research teams will ensure his lasting impact on brain science. Written by: Kresimir Krnjevic *after spending several years in London, A.N. returned to Italy to take up a position as leader of Neuropharmacology group at Sissa, in Trieste #whose flourishing career in studies on cholinergic mechanisms and their impairment in senile dementia was tragically ended when his TWA plane exploded above Long Island Sound in 1996.