dizocilpine-maleate and 4-aminobenzoyl-glycyl-prolyl-leucyl-alanine-hydroxamic-acid

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.

Topics: Analysis of Variance; Animals; Behavior, Animal; Blotting, Northern; Blotting, Western; Cortactin; Dizocilpine Maleate; Electric Stimulation; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Gene Expression Regulation; Hippocampus; Hydroxamic Acids; Immunohistochemistry; Learning; Long-Term Potentiation; Male; Matrix Metalloproteinase 3; Matrix Metalloproteinase 9; Maze Learning; Neuronal Plasticity; Oligodeoxyribonucleotides, Antisense; Oligopeptides; Rats; Rats, Sprague-Dawley; Reaction Time; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spatial Behavior; Time Factors

The interaction between extracellular matrix (ECM) and regulatory matrix metalloproteinases (MMPs) is important in establishing and maintaining synaptic connectivity. By using fluid percussion traumatic brain injury (TBI) and combined TBI and bilateral entorhinal cortical lesion (TBI + BEC), we previously demonstrated that hippocampal stromelysin-1 (MMP-3) expression and activity increased during synaptic plasticity. We now report a temporal analysis of MMP-3 protein and mRNA response to TBI during both degenerative (2 day) and regenerative (7, 15 day) phases of reactive synaptogenesis. MMP-3 expression during successful synaptic reorganization (following unilateral entorhinal cortical lesion; UEC) was compared with MMP-3 expression when normal synaptogenesis fails (after combined TBI + BEC insult). Increased expression of MMP-3 protein and message was observed in both models at 2 days postinjury, and immuohistochemical (IHC) colocalization suggested that reactive astrocytes contribute to that increase. By 7 days postinjury, model differences in MMP-3 were observed. UEC MMP-3 mRNA was equivalent to control, and MMP-3 protein was reduced within the deafferented region. In contrast, enzyme mRNA remained elevated in the maladaptive TBI + BEC model, accompanied by persistent cellular labeling of MMP-3 protein. At 15 days survival, MMP-3 mRNA was normalized in each model, but enzyme protein remained higher than paired controls. When TBI + BEC recovery was enhanced by the N-methyl-D-aspartate antagonist MK-801, 7-day MMP-3 mRNA was significantly reduced. Similarly, MMP inhibition with FN-439 reduced the persistent spatial learning deficits associated with TBI + BEC insult. These results suggest that MMP-3 might differentially affect the sequential phases of reactive synaptogenesis and exhibit an altered pattern when recovery is perturbed.

Topics: Adaptation, Physiological; Analysis of Variance; Animals; Brain Injuries; Disease Models, Animal; Dizocilpine Maleate; Entorhinal Cortex; Functional Laterality; Gene Expression; Gene Expression Regulation; Hydroxamic Acids; Immunohistochemistry; Male; Matrix Metalloproteinase 3; Maze Learning; Microscopy, Electron, Transmission; Neuronal Plasticity; Neuroprotective Agents; Oligopeptides; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Synapses