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1 Neuroscience, Mount Sinai, New York, New York, United States
2 New York, New York, United States; Neuroscience, Mount Sinai, New York, New York, United States
* To whom correspondence should be addressed. E-mail: george.huntley{at}mssm.edu.
Extracellular proteolysis is an important regulatory nexus for coordinating synaptic functional and structural plasticity, but the identity of such proteases is incompletely understood. Matrix metalloproteinases (MMPs) have well-known, mostly deleterious roles in remodeling following injury or stroke, but their role in non-pathological synaptic plasticity and function in intact adult brains has not been extensively investigated. Here, we address the role of MMP-9 in hippocampal synaptic plasticity using both gain- and loss-of-function approaches in urethane-anesthetized adult rats. Acute blockade of MMP-9 proteolytic activity with inhibitors or neutralizing antibodies impairs maintenance, but not induction, of LTP at synapses formed between Schaffer-collaterals and area CA1 dendrites. LTP is associated with significant increases in levels of MMP-9 and proteolytic activity within the potentiated neuropil. By introducing a novel application of gelatin-substrate zymography in vivo, we find that LTP is associated with significantly elevated numbers of gelatinolytic puncta in the potentiated neuropil that codistribute with immunolabeling for MMP-9 and for markers of synapses and dendrites. Such increases in proteolytic activity require NMDA receptor activation. Exposing intact area CA1 neurons to recombinant-active MMP-9 induces a slow synaptic potentiation that mutually occludes, and is occluded by, tetanically-evoked potentiation. Taken together, our data reveal novel roles for MMP-mediated proteolysis in regulating non-pathological synaptic function and plasticity in mature hippocampus.
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