Our topic

Lab members

- BERNARD Anne. Technician.
- CHARTON Gérard. Technician.
- CHARRAT, Eliane. Technician.
- FEHRAT, Lotfi. Researcher INSERM.
- GUEYE Yatma. PhD student.
- KHRESTCHATISKY Michel. Head of the CNRS Research UMR6184. Team co-director.
- OULD-YAHOUI, Adlane. PhD student.
- RIVERA Santiago. Researcher CNRS. Team co-director.
- SBAI Walid. PhD student.
- TREMBLAY Evelyne. Researcher INSERM. 


The Matrix Metalloproteinases (MMPs) and their Endogenous Inhibitors (TIMPs) in the Physiopathology of the Central Nervous System
- The balance between proteinases and inhibitors is a key factor to interpret the physiopathological outcome in many tissues including the central nervous system (CNS). Matrix metalloproteinases (MMPs) regulate by proteolytic cleavage the activity of numerous extracellular (proteoglycans, laminin, collagens) and pericellular (CAMs, cytokine receptors, neurotransmitter receptors…) proteins and thus are critically involved in inter-cellular communication, and particularly in inflammatory processes (see Rivera et al., 2004 Med&Sci).
- Our group has shown for the first time that the MMP/TIMP system is regulated in lesions and tissue remodelling associated with neuronal hyperactivity and excitotoxicity in brain models of epilepsy (Rivera et al., 1997) or global cerebral ischemia (Rivera et al., 2002). We have developed in situ zymography approaches on brain slices and living cells that reveal net proteolytic induction in various neural cell types in the course of pathology (Jourquin et al., 2003). We have identified MMP-9 as a protease involved in excitotoxic neuronal death (Jourquin et al., 2003) and MMP-2 in astrocytes migration in connexion with the actin cytoskeleton and integrins (Ogier et al. 2006). We have also evidence that TIMP-1 deficient mice are resistant to neuronal excitotoxic lesions and show impaired reactive sprouting in epilepsy (Jourquin et al., 2005). In addition, TIMP-1 deficient mice show reduced learning and memory skills when compared to WT mice. Altogether, we have compelling evidence that altering the MMP/TIMP balance, both in vitro and in vivo, has profound effects on the physiopathology of the CNS.
- The objectives of our group are to study the mechanisms whereby MMPs and TIMPs influence pathology, plasticity and repair through the regulation of the neural microenvironment and the interplay between neurons and glial cells. For this purpose, we are using cell biology, molecular biology, functional neuroanatomy, biochemistry, cell imaging and proteomic approaches.

Keywords molecular & cell neurobiology, matrix metalloproteinases, hippocampus, adhesion molecules, extracellular matrix, excitotoxicity, neuroplasticity, sprouting, learning, glia, inflammation, tissue repair

Recent Publications

- Bi R, Rong Y, Bernard A, Khrestchatisky M, Baudry M.(2000). Src-mediated tyrosine phosphorylation of NR2 subunits of N-methyl-D-aspartate receptors protects from calpain-mediated truncation of their C-terminal domains.J Biol Chem. 275:26477-83. PMID : 10846184.
- Rong Y, Lu X, Bernard A, Khrestchatisky M, Baudry M. (2001). Tyrosine phosphorylation of ionotropic glutamate receptors by Fyn or Src differentially modulates their susceptibility to calpain and enhances their binding to spectrin and PSD-95. J Neurochem. 79:382-90. PMID : 11677266.
- Khrestchatisky M and Rivera S (2002). Le double jeu des métalloprotéases. Biofutur.
- Rivera S, Ogier C, Jourquin J, Timsit S, Szklarczyk A.W, Miller K, Gearing A.J.H, Kaczmarek L and Khrestchatisky M. (2002) Gelatinase B and TIMP-1 are regulated in a cell- and time dependent manner in association with neuronal demise and glial reactivity after global forebrain ischemia. Eur J Neurosci. 15 : 19-32. PMID : 11860503.
- Jourquin J, Tremblay E, Décanis N, Charton G, Hanessian S, Chollet A-M, Le Diguardher T, Khrestchatisky M and Rivera S. (2003). Neuronal activity-dependent increase of net matrix metalloproteinase activity is associated with MMP-9 neurotoxicity after kainate. Eur J Neurosci 18:1-11. PMID : 14511330.
- Khrestchatisky K Jourquin J, Ogier C, Charton, Tremblay E et Rivera S (2003) Mes métalloprotéases de la matrice et leurs inhibiteurs, des modulateurs des interactions neuro-immunes et des processus physipathologiques dans le système nerveux. J Soc Biol, 197:133-144.
- Rivera S, Jourquin J, Ogier C, Bernard A, Charton G, Tremblay E et Khrestchatisky M (2004) Le Système MMP/TIMP dans la Physiopathologie du Système Nerveux. Med & Sci 20:55-60. PMID : 14770364.
- Munkeby BH, Borke WB, Bjornland K, Sikkeland LIB, Borge GIA, Lomo J, Rivera S, Khrestchatisky M, Halvorsen, Saugstad OD (2005) Resuscitation of hypoxic piglets with 100% O2 increases pulmonary metalloproteinases and IL-8. Pediatric Res 58:542-548. PMID : 16148071.
- Jourquin J, Tremblay E, Chaillan FA, Marchetti E, Roman F, Soloway PD, Dive V, Yiotakis A, Bernard A, Khrestchatisky M and Rivera S (2005). Tissue inhibitor of metalloproteinases-1 (TIMP-1) modulates neuronal death, axonal plasticity and learning and memory. Eur. J. Neurosci. 22 : 2569-2578. PMID : 16307599.
- Ogier C, Creidy R, Boucraut J, Soloway P, Khrestchatisky M and Rivera S (2005) Astrocyte reactivity to Fas activation is attenuated in TIMP-1 deficient mice. An in vitro study. BMC Neuroscience 6 : 68. PMID : 16316466
- Ogier C, Bernard A, Chollet AM, Le Diguardher T, Hanessian S, Charton C, Khrestchatisky M and Rivera S (2006). Matrix Metalloproteinase-2 (MMP-2) regulates astrocyte motility in connection with the actin cytoskeleton and integrins. Glia (in press).
- F.A. Chaillan, S. Rivera, E. Marchetti, J. Jourquin, P.D. Soloway, Z. Werb, M. Khrestchatisky, and F.S. Roman Involvement of tissue inhibitor of metalloproteinases-1 in learning and memory in mice. (Submitted).


- Zena Werb UCSF, San Francisco, USA http://www.ucsf.edu/pibs/faculty/werb.html
- Paul Soloway Cornell University, Ithaca, NY, USA http://www.people.cornell.edu/pages/pds28/
- Lesczek Kaczmarek, Nencki Institute, Warsaw, Poland http://neurogene.nencki.gov.pl/tiscult.htm
- Vincent Dive, DIEP, CEA/Saclay, France http://www-dsv.cea.fr/content/cea/esp_info/recherche/cea_bio/cea_bio18/dive18.htm
- Berit Munkeby & Ola Didrik Saugstad, Rickhospitalet, Oslo, Norway http://folk.uio.no/olas/CV/CV/cv_1.html
- Stephen Hanessian. University of Montréal, Montréal, Canada. http://osiris.corg.umontreal.ca/
- François Roman, Neurobiologie des Processus Mnésiques – UMR 6149 CNRS, Marseille, France http://www.up.univ-mrs.fr/document.php?pagendx=185&project=umr_6149

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