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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.