M.D., Boston University School of Medicine
A.B., Cornell University
Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that can be released and/or activated in a neuronal activity dependent manner. MMP expression and activity can also be dramatically upregulated with injury, including that mediated by infection or hypoxia. Many studies have therefore focused on their role in brain pathology. Relatively less is known about the role of MMPs in normal CNS physiology, and thus whether critical physiological processes might be disrupted when MMP levels are pathologically elevated.
While recent studies suggest that MMPs play a role in normal learning and memory, the mechanisms by which they do so are not completely understood. Similarly, information related to the question of how excessive MMP activity might contribute to synaptic injury in particular is limited. Our work is focused on the mechanisms by which MMPs influence neuronal and synaptic structure and function. We are particularly interested in their ability to cleave specific synaptic adhesion molecules, and their potential to stimulate signaling by G protein coupled protease activated receptors. Effects on specific adhesion molecules and G protein coupled receptors can in turn influence events, including actin polymerization, that may alter synaptic structure.
MMP mediated effects at the synapse are tested in varied models, including those related to disease. Georgetown collaborators include Dr. Seung Lim.
- Niedringhaus M, Chen X, Dzakpasu R, Conant K. MMPs and soluble ICAM-5 increase neuronal excitability within in vitro networks of hippocampal neurons. PLoS One. 2012;7(8):e42631.
- Conant K, Lonskaya I, Szklarczyk A, Krall C, Steiner J, Maguire-Zeiss K, Lim ST.Methamphetamine-associated cleavage of the synaptic adhesion molecule intercellular adhesion molecule-5. J Neurochem. 2011 Aug;118(4):521-32.
- Conant K, Wang Y, Szklarczyk A, Dudak A, Mattson MP, Lim ST. Matrix metalloproteinase-dependent shedding of intercellular adhesion molecule-5 occurs with long-term potentiation. Neuroscience 2010 Mar 17;166(2):508-21.
- Szklarczyk A, Beique J, Wang Y, Knorr D, Haughey N, Malpica T, Mattson M, Huganir R, andConant K. MMP-7 cleaves the NR1 NMDA receptor subunit and modifies NMDA receptor function. FASEB J 2008 Nov;22(11):3757-67.
- Milward E, Kim K J, Szklarczyk A, Nguyen T, Melli G, Nayak M, Deshpande D, Fitzsimmons C, Hoke A, Kerr D, Griffin J W, Calabresi P A, and Conant K. Cleavage of Myelin Associated Glycoprotein by Matrix Metalloproteinases. Journal of Neuroimmunology 2008 Jan;193 (1-2):140-8.
- Milward, L, Fitzsimmons C, Szklarczyk A, and Conant K. The matrix metalloproteinases and CNS plasticity: An overview. Journal of Neuroimmunology. 2007 Jun 5 187(1-2):9-19
- Szklarczyk A, Stins M, Milward EA, Ryu H, Fitzsimmons C, Sullivan D, and Conant K. Glial activation and matrix metalloproteinase release in cerebral malaria. J Neurovirol.2007;13(1):2-10.
- Szklarczyk A., Oyler G., McKay R., Gerfen C., and Conant K. Cleavage of Neuronal SNAP-25 by Exogenous MMP-7. Journal of Neurochemistry (2007) 102(4):1256-63
- Szklarczyk A, Conant K, Owens D, Ravin R, McKay R and Gerfen C. Matrix metalloproteinase-7 modulates synaptic vesicle recycling and induces atrophy of neuronal synapses.Neuroscience (2007) 149(1):87-98.
- Larson P, Giroux T, Conant K, and Yong VW. Myelin formation during development of the CNS is delayed in matrix metalloproteinase-9 and -12 null mice. Journal of Neuroscience2006 26:2207
- Conant K, St. Hillaire C, Nagase H, Visse R, Gary D, Haughey N, Anderson C, Turchan J, and Nath A. MMP-1 interacts with neuronal integrins and stimulates dephosphorylation of Akt.Journal of Biological Chemistry. 2004 Feb 27;279(9):8056-62.
- Conant K, St. Hillaire C, Anderson C, Galey D, Wang J, and Nath A. HIV-1 Tat and methamphetamine affect the release and activation of matrix degrading proteinases. Journal of Neurovirology. 2004 Feb;10(1):21-8.
- Conant K, Haughey N, Nath A, St. Hillaire C, Gary DS, Pardo CA, Wahl LM, Bilak M, Milward E, and Mattson MP. Matrix metalloproteinase-1 activates a pertussis toxin-sensitive signaling pathway that stimulates the release of matrix metalloproteinase-9. Journal of Neurochemistry. 2002 Aug;82(4):885-93
- Vawter, MP, Usen N, Thatcher L, Ladenheim B, Zhang P, VanderPutten DM, Conant K, Herman MM, van Kammen DP, Sedvall G, Garver DL, and Freed WJ. Characterization of human cleaved N-CAM and Association with Schizophrenia (2001) Experimental Neurology. 172:29-46.
- Vos C, Sjulson L, Nath A, McArthur JC, Pardo C, Rothstein J, Conant K. Cytotoxicity by matrix metalloproteinase 1 in organotypic and dissociated neuronal cultures. Experimental Neurology 163:324-330, 2000.
- Vos C., Gartner S., Ransohoff R.M., McArthur J.C., Wahl L., Sjulson L., Hunter E., and Conant K. Matrix metalloprotease-9 release from monocytes increases as a function of differentiation: implications for neurodegeneration and neuroinflammation. Journal of Neuroimmunology. (2000) 109:221-227
- Conant, K., McArthur, J., Griffin, D., Sjulson, L., Wahl, L., and Irani, D. Cerebrospinal fluid levels of MMP-2, -7, and –9 are elevated in association with HIV dementia. Annals of Neurology. (1999) 46:391-398.