Inhibition of Hippocampal Matrix Metalloproteinase-3 and -9 Disrupts Spatial Memory

doi:10.1155/2007/73813

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Neural Plasticity
Volume 2007 (2007), Article ID 73813, 8 pages
doi:10.1155/2007/73813

Research Article

Inhibition of Hippocampal Matrix Metalloproteinase-3 and -9 Disrupts Spatial Memory

John W. Wright,^1,2,3 Travis E. Brown,^2,3 and Joseph W. Harding^1,2,3

¹Department of Psychology, Washington State University, Pullman 99164-4820, WA, USA
²Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington State University, Pullman 99164-6520, WA, USA
³Programs in Neuroscience and Biotechnology, Washington State University, Pullman 99164-6520, WA, USA

Received 6 July 2006; Revised 21 September 2006; Accepted 26 September 2006

Academic Editor: Carmen Sandi

Copyright © 2007 John W. Wright et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Memory consolidation requires synaptic reconfiguration dependent upon extracellular matrix (ECM) molecules interacting with cell adhesion molecules. Matrix metalloproteinase (MMP) activity is responsible for transient alterations in the ECM that may be prerequisite to hippocampal-dependent learning. In support of this hypothesis we have measured increases in MMP-3 and MMP-9 levels within the hippocampus and prefrontal cortex during Morris water maze training. The present investigation extends these findings by determining that infusion of an MMP inhibitor (FN-439) into the dorsal hippocampus disrupted acquisition of this task. In vitro fluorescence enzyme assays to determine the specificity of FN-439 against the catalytic domains of MMP-3 and MMP-9 indicated mean ± SEM IC50s of 16.2 ± 7.8 and 210.5 ± 37.8 μM, respectively, while in situ zymography using hippocampal sections treated with FN-439 indicated significant reductions in MMP gelatinase activity. These results suggest that compromising the ability of the dorsal hippocampus to reconfigure ECM molecules by inhibiting MMP activity interferes with appropriate spatial memory acquisition, and support a role for hippocampal MMPs in the phenomena of spatial memory acquisition and storage.