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The Journal of Neuroscience, February 15, 2006, 26(7):1923-1934; doi:10.1523/JNEUROSCI.4359-05.2006

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Behavioral/Systems/Cognitive
Matrix Metalloproteinase-9 Is Required for Hippocampal Late-Phase Long-Term Potentiation and Memory

Vanja Nagy,^1 * Ozlem Bozdagi,^1 * Anna Matynia,² Marcin Balcerzyk,³ Pawel Okulski,³ Joanna Dzwonek,³ Rui M. Costa,² Alcino J. Silva,² Leszek Kaczmarek,³ and George W. Huntley¹

¹Fishberg Department of Neuroscience, The Mount Sinai School of Medicine, New York, New York 10029-6574, ²Departments of Neurobiology, Psychiatry, and Psychology, and Brain Research Institute, University of California, Los Angeles, Los Angeles, California 90095, and ³Laboratory of Molecular Neurobiology, Nencki Institute, 02-093 Warsaw, Poland

Correspondence should be addressed to Dr. George W. Huntley, Fishberg Department of Neuroscience, Box 1065, The Mount Sinai School of Medicine, 1425 Madison Avenue, New York, NY 10029-6574. Email: george.huntley{at}mssm.edu

Matrix metalloproteinases (MMPs) are extracellular proteases that have well recognized roles in cell signaling and remodeling in many tissues. In the brain, their activation and function are customarily associated with injury or pathology. Here, we demonstrate a novel role for MMP-9 in hippocampal synaptic physiology, plasticity, and memory. MMP-9 protein levels and proteolytic activity are rapidly increased by stimuli that induce late-phase long-term potentiation (L-LTP) in area CA1. Such regulation requires NMDA receptors and protein synthesis. Blockade of MMP-9 pharmacologically prevents induction of L-LTP selectively; MMP-9 plays no role in, nor is regulated during, other forms of short-term synaptic potentiation or long-lasting synaptic depression. Similarly, in slices from MMP-9 null-mutant mice, hippocampal LTP, but not long-term depression, is impaired in magnitude and duration; adding recombinant active MMP-9 to null-mutant slices restores the magnitude and duration of LTP to wild-type levels. Activated MMP-9 localizes in part to synapses and modulates hippocampal synaptic physiology through integrin receptors, because integrin function-blocking reagents prevent an MMP-9-mediated potentiation of synaptic signal strength. The fundamental importance of MMP-9 function in modulating hippocampal synaptic physiology and plasticity is underscored by behavioral impairments in hippocampal-dependent memory displayed by MMP-9 null-mutant mice. Together, these data reveal new functions for MMPs in synaptic and behavioral plasticity.

Key words: proteolysis; extracellular matrix; integrins; synaptic plasticity; fear conditioning; LTD

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Received Oct. 12, 2005; revised Dec. 10, 2005; accepted Jan. 1, 2006.

Correspondence should be addressed to Dr. George W. Huntley, Fishberg Department of Neuroscience, Box 1065, The Mount Sinai School of Medicine, 1425 Madison Avenue, New York, NY 10029-6574. Email: george.huntley{at}mssm.edu

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