Synaptic homeostatic plasticity maintains firing of neuronal networks within physiological range, by adjusting synaptic strength via molecular and morphological changes in the synapse. The perineuronal extracellular matrix (ECM), which is mainly composed of chondroitin sulfate proteoglycans such as brevican, stabilizes synapses and reduces their plasticity. Previous data indicated that brevican is cleaved during homeostatic plasticity, which may facilitate synapse remodeling. The proteases ADAMTS4, -5 and the closely related ADAMTS8 and -15 may share brevican as substrate for ECM regulation. To elucidate the role of ADAMTSs in homeostatic plasticity, we quantified their expression by qPCR in neurons after prolonged network silencing. Further, we investigated substrate specificity of ADAMTSs in vitro. We used siRNAs to knock-down selected ADAMTSs in neuronal cultures and quantified abundance of specific synaptic proteins regulated during plasticity. We found ADAMTS4 and -5 mRNA to be regulated during homeostatic plasticity and they cleaved brevican in vitro, unlike ADAMTS8 and -15. Expressional or functional interference with ADAMTS5 decreased cleavage of brevican at the peri-synaptic space in neuronal cultures and interfered with homeostatic regulation of synaptic proteins. In line with this finding, homeostatic plasticity driven pre-synaptic functional adjustments were abolished upon ADAMTS5 downregulation. Finally, a treatment with brevican cleavage product triggered synaptic protein regulation in neuronal cultures that mimicked homeostatic plasticity-induced changes, indicating an instructive role of brevican cleavage fragment in this process. In conclusion, we found that ECM remodeling via ADAMTS5-mediated cleavage of brevican is critical for silencing-induced homeostatic regulation of synaptic properties, necessary for stable firing of neuronal networks.