Activity-dependent extracellular proteolytic cascade cleaves the ECM component brevican to promote structural...

The brain's perineuronal extracellular matrix (ECM) is a crucial factor in maintaining the stability of mature brain circuitry. However, how activity-induced synaptic plasticity is achieved in the adult brain with a dense ECM is unclear. We hypothesized that neuronal activity induces cleavage of ECM, creating conditions for synaptic rearrangements. To test this hypothesis, we investigated neuronal activity-dependent proteolytic cleavage of brevican, a prototypical ECM proteoglycan, and the importance of this process for functional and structural synaptic plasticity in the rat hippocampus ex vivo. Our findings reveal that chemical long-term potentiation (cLTP) triggers rapid brevican cleavage in perisynaptic regions through the activation of an extracellular proteolytic cascade involving proprotein convertases and ADAMTS-4 and ADAMTS-5. This process requires NMDA receptor activation and involves astrocytes. Interfering with cLTP-induced brevican cleavage prevents the formation of new dendritic protrusions in CA1 but does not impact LTP induction by theta-burst stimulation of CA3-CA1 synapses. Our data reveal a mechanism of activity-dependent ECM remodeling and suggest that ECM degradation is essential for structural synaptic plasticity.