MMP-9, an extracellular protease in control of synaptic plasticity

The last twenty five years of intense research have provided convincing evidence for a role of regulation of gene expression in control of long-term neuronal plasticity, including learning and memory. Following our discovery (in late eighties) of c-fos activation in those phenomena, it has been well documented that c-Fos and its functional form, AP-1 transcription factor, play the major role learning processes. Recently, an extracellular proteolytic system, composed, inter alia, of tissue inhibitor of matrix metalloproteinases, TIMP-1 and matrix metalloproteinase-9, MMP-9, has emerged as a major AP-1 target in the brain neurons responding to enhanced neuronal activity. Structural remodeling of the dendritic spines and synapses is essential for synaptic plasticity, underlying learning and memory. We have found that in the rodent hippocampus both MMP-9 protein and its transcript are associated with dendritic spines, where they can undergo activity-driven local translation and locally released MMP-9 enzymatic activity controls the morphology of the spines. Functional inactivation of MMP-9 affects synaptic plasticity and blocks late phase of long-term potentiation as well as hippocampus and amygdala-dependent learning. In aggregate, these results point to a novel molecular mechanism of synaptic function that operates extracellularly.