Yves De Koninck, Ph.D., FCAHS, FRSC Professor of Psychiatry & Neuroscience, Laval University Canada Research Chair in Chronic Pain and Related Brain Disorders
Scientific Director, Sentinel North Initiative
Scientific Director, CERVO Brain Research Centre, Quebec Mental Health Institute Director of Research, Quebec Integrated University Health and Social Services Centre
Neuronal chloride homeostasis; from regulation of synaptic plasticity to therapeutic target
A key to the future of chronic pain management is to understand the neurobiological mechanisms that govern how our brain adapts and maladapts to an imbalance in our sensory system because of an injury to our body or a disease condition. This is critical to be able to target the root cause of abnormal, pathological pain for therapeutic development. The drama is that most drugs used for treating chronic pain to date have emerged from off-label use and are therefore not designed to directly address the source the problem. My lab has pursued to identify key mechanisms explaining aberrant pain processing by the nervous system as well as co-morbidities that develop from sustained pain hypersensitivity. This includes the discovery of impaired inhibition resulting from chloride dysregulation in neuropathic pain conditions, leading to cross-talk between sensory channels and ectopic activity possibly underlying spontaneous pain. I will illustrate how such discoveries open new perspectives to understand abnormal pain and how it affects our thinking for therapeutic design. I will also describe how this work has led us to unravel some basic mechanisms underlying the adaptive and maladaptive response to opioid treatment, revealing that opiate tolerance, hyperalgesia and withdrawal result from distinct mechanisms. Each can be targeted independently, without affecting the analgesic effect of opioids, introducing avenues for adjuvant therapies to improve prolonged opioid use. Finally, I will conclude by showing that chloride regulation heterogeneity translates into significant differences in the robustness of inhibition, dramatically affecting metaplasticity at excitatory synapses. Local ionic plasticity thus critically shapes how different components of nociceptive pathways process sensory information.
Wednesday, March 27th, 2019 1:00 - 2:00 pm School of Medicine, Room 132A
Professor Department of Microbiology & Immunology Geisel School of Medicine at Dartmouth Hanover, NH
To Build a Biofilm
Biofilms are surface-attached microbial communities. c-di-GMP is a conserved dinucleotide signal that regulates biofilm formation by bacteria. In Pseudomonas fluorescens, a critical pathway for biofilm formation requires the localization of a larger cell surface adhesion, called LapA, to the cell surface. Localization of LapA is regulated by the dinucleotide signaling molecule c-di-GMP. Synthesis of c-di-GMP by diguanylate cyclases (DGCs) and its degradation by phosphodiesterases (PDEs) is well established, and progress has also been made in elucidating c-di-GMP output systems. For example, our group has characterized a membrane protein, LapD, which binds c-di-GMP via a degenerate PDE domain; this c-di-GMP receptor regulates localization of the LapA adhesin to the cell surface, which is a critical event for biofilm formation by P. fluorescens. A central open question in the field is how bacteria like P. fluorescens and P. aeruginosa, with 50+ proteins that make, break and bind c-di-GMP, coordinate the action of these many proteins to provide a coordinated, c-di-GMP-regulated output. I will discuss two aspects of recent work from the lab: (i) explore mechanisms of c-di-GMP signaling specificity that impact the control of a biofilm adhesin system that is conserved in 500+ bacterial genomes, (ii) describe recent findings demonstrating a novel mechanism whereby the c-di-GMP-regulated adhesin LapA is localized to the surface.