MOLECULAR AND FUNCTIONAL SYNAPTIC ADAPTATIONS DURING HOMEOSTATIC PLASTICITY REQUIRE ECM REMODELING BY ADAMTS-5

Neuronal networks maintain synaptic transmission rates within physiological range through homeostatic plasticity. This process adjusts synaptic strength via molecular and morphological changes of the synapse. The perineuronal extracellular matrix (ECM) stabilizes synapses and reduces their plasticity. Previous data indicated that brevican (BC), a chondroitin sulfate proteoglycan and one of the brain’s main ECM components, is cleaved during homeostatic plasticity, a process that has been suggested to facilitate synapse remodeling. Several members of the ADAMTS family of proteases are known or predicted to cleave BC. In this study, we aimed to determine the impact of BC processing by ADAMTSs on homeostatic plasticity. To this end, we quantified the expression of ADAMTSs by qPCR in neuronal cultures following induced network silencing. We found ADAMTS-4 and -5 mRNA to be upregulated during homeostatic plasticity in vitro. Next, we used siRNAs to knock-down selected ADAMTSs in neuronal cultures and quantified abundance of specific synaptic proteins regulated during homeostatic plasticity. ADAMTS-5 knock-down decreased cleavage of BC at the peri-synaptic space in neuronal cultures and interfered with normal homeostatic regulation of synaptic proteins. In line with this finding, homeostatic plasticity driven pre-synaptic functional adjustments were abolished upon ADAMTS-5 downregulation. Finally, treatments with fragments of BC triggered synaptic protein regulation in neuronal cultures, mimicking homeostatic plasticity-induced changes. This sets BC as a potential extracellular mediator for intracellular adaptations during homeostatic plasticity. In conclusion, we found that ECM remodeling via cleavage of BC by ADAMTS-5 is necessary for silencing-induced homeostatic regulation of synaptic properties.