Research interests
Our research aims to improve our understanding of neuronal synaptic plasticity under different physiological and pathological conditions. Specifically, we seek to elucidate changes in neuronal interconnections, receptor reconfigurations, and interactions with glial cells. Our past, present, and future discoveries are part of the process of developing advanced, effective therapeutics.
[1] The study of synaptic mechanisms in the sensory spinal cord and their plasticity under pathological conditions in experimental models of chronic pain and autism. We have recently shown that promoting neuronal chloride extrusion can rescue and even enhance benzodiazepine site-ligand mediated analgesia (Lorenzo et al., Nature Commun. 2020). This recent advance in benzodiazepine action occurs via pharmacological actions on both α2/α3GABAA receptor subtypes and KCC2 (a potassium chloride cotransporter that maintains neuronal resting potential). This discovery, by combining a lower dose of benzodiazepine with a potassium/chloride transport enhancer, could change the way benzodiazepines are dosed and administered in the future by lowering their effective doses and prolonging their effects. It may even make high doses of benzodiazepines more effective. These results represent an advance in the understanding of the actions and limitations of benzodiazepines and represent an important improvement in their therapeutic action in animals and perhaps in humans in the future…
Next generations of benzodiazepines: new openings and opportunities?
Les benzodiazépines de la prochaine génération: de nouvelles possibilités ?
[2] The differences in the regulatory mechanisms of GABAA receptors, KCC2 and Calcitonin Gene-Related Peptide(CGRP) between male and female animals (Mapplebeck et al., Cell reports 2019; Paige et al., J. Neurosci. 2022) and between men and women (Dedek et al., Brain 2022):
[3] Hyperexcitability and KCC2: the neuronal interaction between NMDA receptors and KCC2 (with Pr Michael Hildebrand and his team, Dedek et al., Brain 2019).
[4] Chloride homeostasis across the superficial dorsal horn (with Francesco Ferrini et al., Nature Commun. 2020). A gradient of KCC2 and its activity can be observed and measured across the spinal superficial dorsal horn. This subtle intracellular Cl- heterogeneity across the superficial dorsal horn neurons critically shapes plasticity for selective nociceptive modalities: the higher propensity to plasticity in lamina I compared to lamina II differentially affects sensitization to thermal and mechanical input. Further investigations are underway…
[5] The involvement of multiple immunoinflammatory mediators in the CNS or periphery in various diseases. The consequences at the level of the spinal cord and brain.
[6] The role of G protein-coupled receptors (GPCRs) such as the neurokinin-1 receptor in nociception and pain transmission (led by Pr Antoine Godin).
In addition to the classical collaborations between biologists and geneticists, our current projects require close interaction with biophysicists, expert microscopists, and mathematicians. We are trying to develop new mathematical and analytical tools that can be broadly applied to biology and neuroscience.
Research areas
Cellular neurobiology, preclinical trials, GABAA receptors, benzodiazepines, glycine receptors, chloride homeostasis, K+/Cl– Cotransporters (NKCC1/KCC2), KCC2 enhancers, new viral vectors, gene therapy, spinal cord, sensory and motor physiology, neuronal excitability, synaptic transmission and plasticity, , GPCR, Neurokinin-1 receptor, neuropharmacology and drug development.
Illnesses under study
Chronic pain, autism, neurodegenration, amyotrophic lateral sclerosis
Technologies
Functional neuronal imaging, immunohisto- and cytochemistry, confocal and electron microscopy, in vivo virology for neuroscience, fluorescence spectroscopy, non-linear microscopy, signal analysis and image analytic tool development, super-resolution microscopy, in vivo and in vitro optogenetics, nanotechnologies, behavioral measurements, neuropharmacology/drug development, preclinical studies, RT-qPCR (Real Time quantitative Polymerase Chain Reaction), RNAscope.