Katherine E. Conant
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, their potential to stimulate signaling by G protein coupled protease activated receptors, and their ability to influence population activity through modulation of the perineuronal net. MMP mediated effects on neuronal structure and function are tested in varied models, including those related to disease. Georgetown collaborators include Drs. Jian Young Wu, Stefano Vicini, John Partridge, Rhonda Dzakpasu, Gerard Ahern, Ken Kellar, Sonia Villapol, and Kathleen Maguire-Zeiss. PhD students include Dr. Megan Allen (former, now at Weill-Cornell), Lorenzo Bozzelli and Seham Alaiyed.
- Proteolysis as a mediator of antidepressant efficacy. Studies are focused on the question of whether proteolysis can stimulate excitatory synapse formation and/or reduce inhibitory input to pyramidal cells.
- Manipulating monoaminergic tone to increase cognitive reserve and reduce amyloid deposition in a mouse model of AD.
- Dysregulated proteolysis in HIV associated neurocognitive disorders.
“‘The more research, the merrier. This is really novel stuff, and could provide some nice new pieces to the puzzle of brain degeneration and its treatment,’ Conant says. ‘Having the support I have had, both through the endowed professorship and from my department chair and my colleagues, has made all the difference.’”
- Bozzelli PL, Alaiyed S, Kim E, Villapol S, and Conant K. Proteolytic Remodeling of Perineuronal Nets: Effects on Synaptic Plasticity and Neuronal Population DynamicsNeural Plasticity, Volume 2018, Article ID 5735789, 13 pages
- Jerome Sun, P. Lorenzo Bozzelli, Adam Caccavano, Megan Allen, Jason Balmuth, Stefano Vicini, Jian-Young Wu*, and Katherine Conant* Disruption of perineuronal nets increases the frequency of sharp wave ripples, Hippocampus. 2018 Jan;28(1):42-52.
- Conant K, Daniele S, Bozzelli PL, Abdi T, Edwards A, Szklarczyk A, Olchefske I, Ottenheimer D, Maguire-Zeiss K.Matrix metalloproteinase activity stimulates N-cadherin shedding and the soluble N-cadherin ectodomain promotes classical microglial activation. J Neuroinflammation. 2017 Mar 17;14(1):56. doi: 10.1186/s12974-017-0827-4.
- Li Y, Chen X, Dzakpasu R, Conant K. Dopamine-dependent effects on basal and glutamate stimulated network dynamics in cultured hippocampal neurons. J Neurochem. 2017 Feb;140(4):550-560. doi: 10.1111/jnc.13915. Epub 2017 Jan 12.
- Allen M, Ghosh S, Ahern GP, Villapol S, Maguire-Zeiss KA, . Protease induced plasticity: matrix metalloproteinase-1 promotes neurostructural changes through activation of protease activated receptor 1. Sci Rep. 2016 Oct 20;6:35497. doi: 10.1038/srep35497.
- Valente M, Allen M, Lim ST, *Conant K, *Grilli M. The MMP-1/PAR-1 axis enhances proliferation and neuronal differentiation of adult hippocampal neural progenitor cells, Neural Plasticity 2015;2015:646595 PMID:26783471
- Li Y, Partridge J, Berger C, Sepulveda-Rodriguez A, Vicini S, Conant K. Dopamine increases NMDA-stimulated calcium flux in striatopallidal neurons through a matrix metalloproteinase-dependent mechanism. Eur J Neurosci. 2016 Jan;43(2):194-203. PMID: 26660285
- Conant K, Allen M, Lim ST. Activity dependent CAM cleavage and neurotransmission. Frontiers in Molecular Neuroscience, 2015 Aug 11;9:305. PMID:26321910
- Lonskaya I, Partridge J, Lalchandani RR, Chung A, Lee T, Vicini S, Hoe H, Lim ST, Conant K. Soluble ICAM-5, a product of activity dependent proteolysis, increases mEPSC frequency and dendritic expression of GluA1. PLosOne 2013 Jul 2;8(7). e69136 doi: 10.1371/journal.pone.0069136. PMID:23844251 PMCID:PMC3699500
- Niedringhaus M, Chen X, Conant K, Dzakpasu R. Synaptic potentiation facilitates memory-like attractor dynamics in cultured in vitro hippocampal networks. PLoS One. 2013;8(3):e57144. doi: 10.1371/journal.pone.0057144. Epub 2013 Mar 20. PMID: 23526935. PMCID:PMC3603961
- 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, and Conant 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):2-118.
- 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. 172:29-46.25.
- 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.