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The Journal of Neuroscience, November 12, 2003, 23(32):10182-10189

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Development/Plasticity/Repair
Matrix Metalloproteinase Inhibition Alters Functional and Structural Correlates of Deafferentation-Induced Sprouting in the Dentate Gyrus

Thomas M. Reeves,¹ Mayumi L. Prins,³ JiePei Zhu,² John T. Povlishock,¹ and Linda L. Phillips¹

Departments of ¹Anatomy and Neurobiology and ²Anesthesiology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298, and ³Division of Neurosurgery, University of California at Los Angeles, Los Angeles, California 90095

Molecules comprising the extracellular matrix (ECM), and the family of matrix metalloproteinases (MMPs) that regulate them, perform essential functions during neuroplasticity in both developing and adult nervous systems, including substrate guidance during neuritogenesis and the establishment of boundaries for axonal terminal fields. MMP proteolysis of ECM molecules may perform a permissive or inductive role in fiber remodeling and synaptogenesis initiated by deafferentation. This study examined functional and structural effects of MMP inhibition during the early phases of deafferentation-induced sprouting, characterizing components of the degeneration/proliferation cycle that may be dependent on MMP activity. Adult rats received unilateral lesions of the entorhinal cortex to induce collateral sprouting of the crossed temporodentate fiber pathway. This was followed by intraventricular infusion of the MMP inhibitor FN-439 (2.9 mg/kg) or saline vehicle. After 7 d postlesion, rats underwent in vivo electrophysiological recording or histological processing for electron microscopic analysis. Lesioned rats receiving vehicle exhibited normal sprouting and synaptogenesis, with the emergence of the capacity for long-term potentiation (LTP) within the sprouting pathway, and the successful clearance of degenerating terminals with subsequent synaptic proliferation. In contrast, lesioned rats receiving the MMP inhibitor failed to develop the capacity for LTP and showed persistent cellular debris. Current source density analysis also revealed an FN-439-induced disruption of the current sink, normally localized to the middle region of the granule cell dendrites, corresponding to the terminal field of the crossed temporodentate fibers. These results establish a role for MMP-dependent processes in the deafferentation/sprouting cycle.

Key words: deafferentation; collateral sprouting; synaptogenesis; matrix metalloproteinase; extracellular matrix; synaptic plasticity

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Received July 10, 2003; revised September 5, 2003; accepted September 7, 2003.

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