MAR 19, 2014 10:00 AM PDT

NMDA receptor regulation in health and disease

Presented At Neuroscience
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  • Head and Senior Scientist of Neurosciences & Mental Health, Associate Chief of Science Strategy Research, Sick Kids Research Institute
      Dr. Michael Salter is Senior Scientist in the Neurosciences & Mental Health Program at The Hospital for Sick Children (SickKids) Research Institute, and a professor at the University of Toronto. He holds the Canada Research Chair in Neuroplasticity and Pain, and is the Anne and Max Tanenbaum Chair in Molecular Medicines. He has authored more than 120 scientific papers, reviews and book chapters. Dr. Salter is best known for his work on synaptic physiology and he has done groundbreaking work that has led to new paradigms about neuroplasticity and about how synaptic transmission in the central nervous system is regulated by biochemical processes within neurons and by glial-neuronal interactions. His discoveries have broad implications for the control of cell-cell communication throughout the nervous system and his work has regularly appeared in elite journals including Nature, Science, Cell, Nature Medicine and Neuron. Notwithstanding his present focus on molecular/cellular aspects of pain he has published work on many aspects of the pain experience including clinical studies on bio-behavioural aspects of chronic pain in patients. Dr. Salter received an MD degree from the University of Western Ontario in 1982 and went on to obtain a PhD in Physiology from McGill in 1987. After post-doctoral training at Toronto Western and Mt. Sinai hospitals he joined the Research Institute at SickKids in 1990, with an academic appointment in the Department of Physiology at the University of Toronto. He moved rapidly through the ranks and is currently Head of the Neurosciences & Mental Health Program and Associate Chief, Science Strategy at SickKids, and a Professor of Physiology, IMS and Dentistry at UofT. Dr. Salter was the founding Director of the University of Toronto Centre for the Study of Pain an initiative which spans the Faculties of Medicine, Nursing, Dentistry and Pharmacy. In the Centre, he brought together a diverse group of more than 60 pain researchers and academics in the University of Toronto community. Dr. Salter is also a founder and Vice-President of NoNO Inc. a biotechnology company based in Toronto that is developing novel therapeutic agents for the treatment of stroke, neurodegeneration, neurotrauma and pain by targeting protein-protein interactions within neurons in the brain and spinal cord.


    Neuron-glial interactions are increasingly recognized as being key for physiological and pathological processes in the central nervous system. Microglia have been found to play a causal role in neuropathic pain behaviours resulting from peripheral nerve injury, and a core neuron-microglia-neuron signaling pathway has been elucidated. Within the dorsal horn, microglia suppress neuronal inhibition by a cascade involving activation of microglial P2X4 receptors causing the release of brain derived neurotrophic factor (BDNF). BDNF acts on trkB receptors which leads to a rise in intracellular chloride concentration in dorsal horn nociceptive output neurons, transforming the response properties of these neurons. In addition to suppressing inhibition, peripheral nerve injury causes activity-dependent facilitation at dorsal horn glutamatergic synapses which enhances nociceptive transmission. This enhancement is mediated by intracellular signaling networks involving serine/threonine and tyrosine kinases within nociceptive transmission neurons. Key for this enhancement is facilitation of NMDA receptor function by Src family tyrosine kinases. Microglia-to-neuron signaling is not only critical for pain hypersensitivity after peripheral nerve injury but also for the paradoxical hyperalgesic effect of morphine and other opioids. We anticipate that by targeting microglia-neuron signaling pathways new therapeutic strategies for chronic pain as well as its comorbid sequelae may be developed.

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