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Activity-dependent extracellular proteolytic cascade remodels ECM to promote structural plasticity

Singh, J. B.; Perello Amoros, B.; Schneeberg, J.; Seidenbecher, C. I.; Fejtova, A.; Dityatev, A.; Frischknecht, R.

2024-10-29 neuroscience
10.1101/2024.10.28.620597 bioRxiv
Show abstract

The brains perineuronal extracellular matrix (ECM) is a crucial factor in maintaining the stability of mature brain circuitry. However, how is activity-induced synaptic plasticity achieved in the adult brain with a dense ECM? We hypothesized that neuronal activity induces cleavage of ECM components, creating space for synaptic rearrangements. To test this hypothesis, we investigated neuronal activity-dependent proteolytic cleavage of brevican, a prototypical perineuronal ECM proteoglycan, and its importance of this process for functional and structural synaptic plasticity in the rat hippocampus ex vivo. Our findings revealed that chemical long-term potentiation (cLTP) triggers a rapid brevican cleavage through the activation of an extracellular proteolytic cascade involving proprotein convertases and ADAMTS-4 and ADAMTS-5. This process is dependent on NMDA receptors and requires astrocytes. Interestingly, the extracellular full-length brevican increases upon cLTP, indicating a simultaneous secretion of ECM components. Interfering with cLTP-induced brevican cleavage did not impact the early LTP but prevented formation of new dendritic protrusions. Collectively, these results reveal a mechanism of activity-dependent ECM remodeling and suggest that ECM degradation is essential for structural synaptic plasticity.

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