Microglial depletion increases aggrecan and hyaluronan levels in the diffuse and aggregated extracellular matrix of the mouse brain

The extracellular matrix (ECM) in the brain can be divided into aggregated ECM, such as perineuronal nets (PNNs) around neurons, and diffuse ECM, which is present throughout the brain parenchyma. Both aggregated and diffuse ECM restrict synaptic plasticity and stabilize neural circuits in the adult brain. Hyaluronan (HA) acts as a scaffold for the brain ECM, and multiple proteoglycans, such as aggrecan, bind to HA to form a macromolecular complex. Recent evidence suggests that microglia, the resident immune cells of the brain, play a crucial role in ECM homeostasis. However, it remains unclear how microglia influence the molecular composition of the ECM. Using a tissue-clearing technique and histochemical analysis, we found that microglial depletion increased the staining intensity of aggrecan and HA in both PNNs and diffuse ECM. Biochemical analyses further confirmed the accumulation of the aggrecan core protein and HA following microglial depletion. Our findings highlight the essential role of microglia in regulating the ECM composition and provide new insights into the mechanisms by which microglia influence neuronal function.