Extracellular matrix remodeling during aging aligns with synapse, microglia, and cognitive status

Abstract Synapse dysfunction is tightly linked to cognitive changes during aging, but underlying mechanisms driving dysfunction are minimally understood. The extracellular matrix (ECM) can potently regulate synapse integrity and plasticity. Yet the status of the brain ECM during aging remains virtually unexplored. Using novel ECM-optimized proteomic workflows, we discovered striking regional differences in ECM composition and aging-induced ECM remodeling. ECM status was also aligned with preserved synapse protein abundance across key basal ganglia nuclei. Moreover, using foraging-based behavioral paradigms and confocal imaging in fixed tissue, we demonstrated that reduced ECM-synapse remodeling and microglial aging phenotypes are both linked with deficits in goal-directed behavior in aging mice. Finally, using mouse models of microglia ablation and premature microglial aging, we identified microglial aging phenotypes that promote ECM deposition and synapse numbers. Together, these foundational observations implicate glial-ECM interactions in the regulation of synapse function and cognitive abilities across the lifespan.