Salah El Mestikawy, PhD
Contact
salah.elmestikawy@mcgill.ca
6875 Boulevard LaSalle
Montréal, QC
H4H 1R3
Office:E-3213, Perry Pavilion
Office phone: (514) 761-6131 x6151
Fax: (514) 762-3034
Researcher, Douglas Research Centre
Full Professor, Department of Psychiatry, McGill University
Lab name: Glutamatergic systems in normal and pathological brains
Theme-Based Group: Stress, Anxiety, Depression, and SuicideDivision: Basic Neuroscience
Our team investigates glutamatergic systems in normal and pathological brains of rodent and humans.
- Glutamate is the major excitatory transmitter in the brain. Before its exocytotic release glutamate is uploaded inside synaptic vesicles by carriers named VGLUT1-3. These transporters are key anatomical and functional markers of glutamatergic transmission [1].
• VGLUTs are distributed in distinct neuronal populations. VGLUT1 and VGLUT2 are synthesized by glutamatergic neurons from cortical and subcortical areas [2]. Surprisingly, the atypical subtype VGLUT3 is expressed by cholinergic interneurons from the striatum, a subpopulation of GABAergic interneurons from the cortex and the hippocampus and in a subpopulation of serotoninergic neurons [3]. - This distribution suggests the existence of glutamate cotransmission with acetylcholine (ACh) or serotonin(5-HT) or even GABA and brought up numerous questions on the physiological and pathophysiological implication of VGLUT3 [1].
- Our major objective is to understand the functional implication of VGLUT3-positive neurons in mouse models of psychiatric disorders. Our current research is focused on the role of ACh/glutamate cotransmission, in habit formation, eating disorders, addiction and obsessive-compulsive disorders[4].
- We work with genetic rodent models (biochemistry, molecular biology, anatomy, electrophysiology, opto and pharmacogenetic, fiber photometry, behavior).
- We also collaborate closely with teams of psychiatrists who test our hypotheses and new drugsresulting from our investigations.
• In 2015 we discovered a point mutation of VGLUT3 (p.T8I) in patients suffering of severe addiction or eating disorders [5]. A mouse model was developed (VGLUT3T8I/T8I mice) and used to unravel a mechanism underlying anorexia nervosa and a treatment [6]. - This new drug was proven effective in 20 anorexic patients.
- Double blind randomized clinical trials are currently underway.
- We predict that the same neurobiological mechanism is involved in all eating disorders, in substance use disorders (addiction) and in obsessive-compulsive disorders.
- We expect that the treatment that we discovered will be efficient in all these compulsive disorders.
- We hope that this program will help to increase our understanding of psychiatric disorders and also open new avenue for novel science-based treatments.
Videos
We are committed to sharing our findings as widely as possible and have created several videos (see below) to illustrate our findings.
References
[1] S. El Mestikawy, A. Wallen-Mackenzie, G.M. Fortin, L. Descarries, and L.E. Trudeau, From glutamate co-release to vesicular synergy: vesicular glutamate transporters. Nat Rev Neurosci 12 (2011) 204-16.
[2] E. Herzog, G.C. Bellenchi, C. Gras, V. Bernard, P. Ravassard, C. Bedet, B. Gasnier, B. Giros, and S. El Mestikawy, The existence of a second vesicular glutamate transporter specifies subpopulations of glutamatergic neurons. J Neurosci 21 (2001) RC181.
[3] C. Gras, E. Herzog, G.C. Bellenchi, V. Bernard, P. Ravassard, M. Pohl, B. Gasnier, B. Giros, and S. El Mestikawy, A third vesicular glutamate transporter expressed by cholinergic and serotoninergic neurons. J Neurosci 22 (2002) 5442-51.
[4] M. Favier, H. Janickova, D. Justo, O. Kljakic, L. Runtz, J.Y. Natsheh, T.A. Pascoal, J. Germann, D. Gallino, J.I. Kang, X.Q. Meng, C. Antinora, S. Raulic, J.P. Jacobsen, L. Moquin, E. Vigneault, A. Gratton, M.G. Caron, P. Duriez, M.P. Brandon, P.R. Neto, M.M. Chakravarty, M.M. Herzallah, P. Gorwood, M.A. Prado, V.F. Prado, and S. El Mestikawy, Cholinergic dysfunction in the dorsal striatum promotes habit formation and maladaptive eating. J Clin Invest 130 (2020) 6616-6630.
[5] D.Y. Sakae, F. Marti, S. Lecca, F. Vorspan, E. Martin-Garcia, L.J. Morel, A. Henrion, J. Gutierrez-Cuesta, A. Besnard, N. Heck, E. Herzog, S. Bolte, V.F. Prado, M.A. Prado, F. Bellivier, C.B. Eap, S. Crettol, P. Vanhoutte, J. Caboche, A. Gratton, L. Moquin, B. Giros, R. Maldonado, S. Daumas, M. Mameli, S. Jamain, and S. El Mestikawy, The absence of VGLUT3 predisposes to cocaine abuse by increasing dopamine and glutamate signaling in the nucleus accumbens. Mol Psychiatry 20 (2015) 1448-59.
[6] M. Favier, E. Martin Garcia, R. Icick, C. de Almeida, J. Jehl, M. Desplanque, J. Zimmermann, A. Henrion, N. Mansouri-Guilani, C. Mounier, S. Ribeiro, F. Henderson, A. Geoffroy, S. Mella, O. Poirel, V. Bernard, V. Fabre, Y. Li, C. Rosenmund, S. Jamain, F. Vorspan, A. Mourot, P. Duriez, L. Pinhas, R. Maldonado, N. Pietrancosta, S. Daumas, and S. El Mestikawy, The human VGLUT3-pT8I mutation elicits uneven striatal DA signaling, food or drug maladaptive consumption in male mice. Nat Commun 15 (2024) 5691.
- Ph. D. in Neurosciences, Université P&M Curie, Paris, France, 1982
- Habilitation à diriger des recherches, Université P&M Curie, Paris, France, 1991
- Permanent position at the Centre National de la Recherche Scientifique (CNRS), France, 1983
- Promoted Chargé de recherche 1ère classe, 1987
- Promoted Directeur de recherche 2ième classe, 1995
- Professor, McGill University (Canada Research Chair), 2008
- Promoted Directeur de recherche 1ère classe, 2012-2023
- Currently Directeur de recherche émérite
- 1978-1979, Laboratoire de Biochimie Cellulaire, Collège de France, Paris, Master of Science
- 1979-1985 INSERM U114, Collège de France, Paris, PhD
- 1985-1990 INSERM U288, Faculté de Médecine Pitié-Salpêtrière, Paris,
- 1990-1992 Dept of Cell Biology, Duke University, Durham, NC, USA, Postdoctoral training
- 1992-1998 INSERM U288, Faculté de Médecine Pitié-Salpêtrière, Paris,
- 1998- 2007 INSERM U513, Faculté de Médecine de Créteil, France
- 2007- 2023 INSERM U952, CNRS UMR 7224, UPMC, Paris
- 2008- Currently, Douglas Research Center, Dept of Psychiatry, McGill University, Montreal, Canada
Héloise Hamelin (Postdoc)
Emily Ducharme (Master student)
Érika Vigneault (Technician/lab manager)
Yeqing Geng (Technician/lab manager)
Key publications
- Favier M, Janickova H, Justo D, Kljakic O, Runtz L, Natsheh JY, Pascoal TA, Germann J, Gallino D, Kang JI, Meng XQ, Antinora C, Raulic S, Jacobsen JP, Moquin L, Vigneault E, Gratton A, Caron MG, Duriez P, Brandon MP, Neto PR, Chakravarty MM, Herzallah MM, Gorwood P, Prado MA, Prado VF, El Mestikawy S. Cholinergic dysfunction in the dorsal striatum promotes habit formation and maladaptive eating. The Journal of Clinical Investigation 2020 ; PMID:33164988.
- Sakae DY, Ramet L, Henrion A, Poirel O, Jamain S, El Mestikawy S, Daumas S. Differential expression of VGLUT3 in laboratory mouse strains: Impact on drug-induced hyperlocomotion and anxiety-related behaviors. Genes, brain, and behavior 2019 ; PMID:30324647.
- Vigneault É, Poirel O, Riad M, Prud’homme J, Dumas S, Turecki G, Fasano C, Mechawar N, El Mestikawy S. Distribution of vesicular glutamate transporters in the human brain. Frontiers in neuroanatomy 2015 ; PMID:25798091.
- El Mestikawy S, Wallén-Mackenzie A, Fortin GM, Descarries L, Trudeau LE. From glutamate co-release to vesicular synergy: vesicular glutamate transporters. Nature reviews. Neuroscience 2011 ; PMID:21415847.
- Amilhon B, Lepicard E, Renoir T, Mongeau R, Popa D, Poirel O, Miot S, Gras C, Gardier AM, Gallego J, Hamon M, Lanfumey L, Gasnier B, Giros B, El Mestikawy S. VGLUT3 (vesicular glutamate transporter type 3) contribution to the regulation of serotonergic transmission and anxiety. The Journal of neuroscience 2010 ; PMID:20147547.
- Kashani A, Lepicard E, Poirel O, Videau C, David JP, Fallet-Bianco C, Simon A, Delacourte A, Giros B, Epelbaum J, Betancur C, El Mestikawy S. Loss of VGLUT1 and VGLUT2 in the prefrontal cortex is correlated with cognitive decline in Alzheimer disease. Neurobiology of aging 2008; PMID:17531353.
- Gras C, Amilhon B, Lepicard EM, Poirel O, Vinatier J, Herbin M, Dumas S, Tzavara ET, Wade MR, Nomikos GG, Hanoun N, Saurini F, Kemel ML, Gasnier B, Giros B, El Mestikawy S. The vesicular glutamate transporter VGLUT3 synergizes striatal acetylcholine tone. Nature neuroscience 2008; PMID:18278042.
- Kashani A, Betancur C, Giros B, Hirsch E, El Mestikawy S. Altered expression of vesicular glutamate transporters VGLUT1 and VGLUT2 in Parkinson disease. Neurobiology of aging 2007; PMID:16563567.
- Gras C, Herzog E, Bellenchi GC, Bernard V, Ravassard P, Pohl M, Gasnier B, Giros B, El Mestikawy S. A third vesicular glutamate transporter expressed by cholinergic and serotoninergic neurons. The Journal of neuroscience 2002; PMID:12097496.
- Favier M, Martin Garcia E, Icick R, de Almeida C, Jehl J, Desplanque M, Zimmermann J, Henrion A, Mansouri-Guilani N, Mounier C, Ribeiro S, Henderson F, Geoffroy A, Mella S, Poirel O, Bernard V, Fabre V, Li Y, Rosenmund C, Jamain S, Vorspan F, Mourot A, Duriez P, Pinhas L, Maldonado R, Pietrancosta N, Daumas S, El Mestikawy S. The human VGLUT3-pT8I mutation elicits uneven striatal DA signaling, food or drug maladaptive consumption in male mice. Nature Communication 2024 ; PMID: 38971801
Lab images - click to view:
Video
In 2020, we published article entitled, “Cholinergic dysfunction in the dorsal striatum promotes habit formation and maladaptive eating,” which has also been adapted as a graphical abstract and a video abstract that you can check out below :
In 2024 we published an article entitled “The human VGLUT3-pT8I mutation elicits uneven striatal DA signaling, food or drug maladaptive consumption in male mice.” which led to a video in the program “Découverte” from Radio Canada (https://ici.radio-canada.ca/tele/decouverte/site/episodes/669043/decouverte-anorexie-trouble-alimentaire-traitement). Bouchra Ouatik. Réalisation : Sylvain Caron.
Salah El Mestikawy contributed to a Youtube video from Scilabus (Viviane Lalande) in collaboration with MAAD digital.