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

[摘要] 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 andprefrontal cortex during Morris water maze training. The present investigation extends these findings bydetermining that infusion of an MMP inhibitor (FN-439) into the dorsal hippocampus disrupted acquisitionof this task. In vitro fluorescence enzyme assays to determine the specificity of FN-439against the catalytic domains of MMP-3 and MMP-9 indicated mean±SEMIC50sof 16.2±7.8 and 210.5±37.8μM,respectively, while in situ zymography using hippocampal sections treated with FN-439 indicated significantreductions in MMP gelatinase activity. These results suggest that compromising the ability of the dorsalhippocampus to reconfigure ECM molecules by inhibiting MMP activity interferes with appropriate spatialmemory acquisition, and support a role for hippocampal MMPs in the phenomena of spatial memory acquisitionand storage.

[学科分类] 精神健康和精神病学