Extracellular proteolytic cascade remodels the ECM to promote structural plasticity

Learning and memory formation require activity-dependent rearrangements of neuronal networks driven by structural plasticity. The brain's perineuronal extracellular matrix (ECM), composed mainly of chondroitin sulfate proteoglycans from the lectican family, suppresses structural plasticity in the mature brain. Several members of this family, such as aggrecan and brevican, undergo proteolytic cleavage by proteases from the ADAMTS family, which may loosen the ECM structure. Therefore, we hypothesize that activity-dependent extracellular proteolysis weakens the ECM, supporting neuronal plasticity in the adult brain. To test this hypothesis, we investigated activity-dependent proteolytic cleavage of brevican in the hippocampus ex vivo. Chemical LTP (cLTP) was induced, and Western blot experiments were performed to measure brevican cleavage. The result showed a significant increase in brevican cleavage after cLTP induction. Cleavage was reduced to basal levels in the presence of a broad-spectrum metalloprotease inhibitor or specific ADAMTS-4 and -5 inhibitors. Additional experiments indicate that NMDA receptors and proprotein convertases play a crucial role in ADAMTS-4 and -5 activities. Furthermore, a significant increase in the abundance of the full-length protein was observed, indicating its activity-dependent secretion. Inhibition of ADAMTS did not affect LTP induction, but it prevented the formation of dendritic spines induced by cLTP. These findings suggest a sequence of events that leads to ECM degradation, followed by its restoration, which is necessary for structural plasticity but not for LTP induction.