Microglia promote extracellular matrix deposition and restrict excitatory synapse numbers in the mesolimbic dopamine system during healthy aging

Synapse dysfunction has been definitively linked to cognitive impairments in the aging brain, and microglial physiology has emerged as a robust regulator of synapse status and cognitive aging outcomes. Hippocampal microglia have recently been shown to regulate synapse function via targeted remodeling of the extracellular matrix (ECM), yet the degree to which microglia-ECM interactions impact synapse function in the healthy aged brain remains virtually unexplored. This study combines high-resolution imaging and ECM-optimized tissue proteomics to examine the impact that microglial physiology has on ECM and synapse status in the basal ganglia of healthy aging mice. Our results demonstrate that deposition of the ubiquitous ECM scaffold hyaluronan increases during aging in the ventral tegmental area (VTA), but not its downstream target, the nucleus accumbens, and that VTA microglial tissue coverage correlates with local hyaluronan deposition. Proteomic mapping of core matrisome proteins showed prominent regional differences in ECM composition across basal ganglia nuclei that were significantly associated with abundance of chemokine receptors and synapse proteins. Finally, manipulation of microglial fractalkine signaling through Cx3Cr1 receptor deletion reversed age-associated ECM accumulation within the VTA and resulted in abnormally elevated synapse numbers in this brain region by middle age. These findings indicate that microglia promote age-related increases in ECM deposition in some, but not all, brain regions that may restrict local excitatory synapse numbers. This microglial function could represent an adaptive response to brain aging that helps to maintain appropriate activity patterns within basal ganglia circuits. ### Competing Interest Statement The authors have declared no competing interest.