MMP-9/TIMP-1 Extracellular Proteolytic System as AP-1 Target in Response to Neuronal Activity

  • Grzegorz M. Wilczynski
  • Leszek Kaczmarek


For the last several years, a considerable body of evidence has been collected indicating that MMP-9-mediated TIMP-1-regulated extracellular proteolysis is a novel mechanism contributing to synaptic plasticity. An outstanding feature of this system is that it is kept under the genetic control of a transcription factor AP-1. Both MMP-9 and TIMP-1 are AP-1 target genes in brain and their expression correlates with a spatiotemporal expression pattern of c-Fos, the major neuronal activity-driven component of AP-1. Interestingly, following the gene transcription, MMP-9 mRNA undergoes activity-driven dendritic transport, a feature that is widely accepted as one of the fundamental mechanisms of plasticity. The MMP-9/TIMP-1 system appears to be involved in a broad range of physiological and pathological phenomena in various brain regions. These include developmental reorganization of the cerebellum and visual cortex, hippocampus-dependent learning and long-term-potentiation, as well as pathogenesis of temporal lobe epilepsy. In the hippocampus, MMP-9 appears to function through a direct effect on dendritic spines. We propose an existence of a functional axis, consisting of AP-1/MMP-9/TIMP-1, together with a yet-to-be-discovered synaptic substrate(s) of MMP-9 that has a special liaison with neuronal activity. First, it is activity-driven, and second, it carries on the activity signal to produce its effects on synaptic remodeling and subsequent plasticity.


Dentate Gyrus Dendritic Spine Temporal Lobe Epilepsy Kainic Acid Extracellular Proteolysis 
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Authors and Affiliations

  • Grzegorz M. Wilczynski
  • Leszek Kaczmarek

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