human amygdala CS-56 enrichment LC-MS/MS

Experience-dependent learning depends on synaptic plasticity. Recent findings show that effective integration of novel salient information requires coordinated processes of homo- and hetero- synaptic plasticity onto neighboring dendritic branches. In this work, we hypothesized that activity-dependent remodeling of the peri-synaptic extracellular matrix (ECM) contributes to this mechanism. We show that clusters of the peri-synaptic ECM proteoglycans, containing 6- and 2,6-sulfated chondroitin sulfates recognized by CS56 antibody, emerge in response to sensory stimuli, showing temporal and spatial coincidence with dendritic spine plasticity. CS56 co-immunoprecipitation of synaptosomal proteins identified several CS56-carrying/binding synaptic molecules that are implicated in Ca2+ signaling, vesicles cycling and AMPA-receptor exocytosis, thus suggesting their pivotal role in long-term potentiation (LTP). Finally, we demonstrated that the attenuation of CS56 glycoepitopes in the CA1 hippocampal region, through the depletion of versican as one of its main carriers, impairs LTP and object location memory in adult mice. These findings show that specific ECM glycans regulates the molecular mechanisms underlying induction and consolidation of synaptic plasticity, confirming that experience-dependent refinement of the brain ECM plays a critical role in learning and memory.