Abstract
Rats learning the Morris water maze exhibit hippocampal changes in synaptic morphology and physiology that manifest as altered synaptic efficacy. Learning requires structural changes in the synapse, and multiple cell adhesion molecules appear to participate. The activity of these cell adhesion molecules is, in large part, dependent on their interaction with the extracellular matrix (ECM). Given that matrix metalloproteinases (MMPs) are responsible for transient alterations in the ECM, we predicted that MMP function is critical for hippocampal-dependent learning. In support of this, it was observed that hippocampal MMP-3 and -9 increased transiently during water maze acquisition as assessed by western blotting and mRNA analysis. The ability of the NMDA receptor channel blocker MK801 to attenuate these changes indicated that the transient MMP changes were in large part dependent upon NMDA receptor activation. Furthermore, inhibition of MMP activity with MMP-3 and -9 antisense oligonucleotides and/or MMP inhibitor FN-439 altered long-term potentiation and prevented acquisition in the Morris water maze. The learning-dependent MMP alterations were shown to modify the stability of the actin-binding protein cortactin, which plays an essential role in regulating the dendritic cytoskeleton and synaptic efficiency. Together these results indicate that changes in MMP function are critical to synaptic plasticity and hippocampal-dependent learning.
Publication types
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Comparative Study
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Analysis of Variance
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Animals
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Behavior, Animal / drug effects
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Blotting, Northern
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Blotting, Western / methods
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Cortactin / metabolism
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Dizocilpine Maleate / pharmacology
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Electric Stimulation / methods
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Enzyme Inhibitors / pharmacology
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Excitatory Amino Acid Antagonists / pharmacology
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / physiology
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Hippocampus / drug effects
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Hippocampus / physiology
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Hydroxamic Acids / pharmacology
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Immunohistochemistry / methods
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Learning / drug effects
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Learning / physiology*
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Long-Term Potentiation / drug effects
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Long-Term Potentiation / radiation effects
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Male
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Matrix Metalloproteinase 3 / chemistry
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Matrix Metalloproteinase 3 / physiology*
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Matrix Metalloproteinase 9 / chemistry
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Matrix Metalloproteinase 9 / physiology*
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Maze Learning / drug effects
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Maze Learning / physiology
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Neuronal Plasticity / drug effects
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Neuronal Plasticity / physiology*
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Oligodeoxyribonucleotides, Antisense / pharmacology
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Oligopeptides / pharmacology
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RNA, Messenger / biosynthesis
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Rats
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Rats, Sprague-Dawley
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Reaction Time / drug effects
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Reverse Transcriptase Polymerase Chain Reaction / methods
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Spatial Behavior / drug effects
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Spatial Behavior / physiology*
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Time Factors
Substances
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4-aminobenzoyl-glycyl-prolyl-leucyl-alanine hydroxamic acid
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Cortactin
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Enzyme Inhibitors
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Excitatory Amino Acid Antagonists
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Hydroxamic Acids
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Oligodeoxyribonucleotides, Antisense
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Oligopeptides
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RNA, Messenger
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Dizocilpine Maleate
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Matrix Metalloproteinase 3
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Matrix Metalloproteinase 9