Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease

Huntington's is associated With a reactive microglial response and consequent irlflan nation. To address the rule of these cells in disease pathogenesis, we depleted microglia from R6/2 mice, a rapidly progressing model of Huntington's disease marked by behavioural impairment, mutant huntingtin (mHTT) accumulation, and early death, through colony-stimulating factor 3 receptor inhibition (CSF1Ri) with pexidartinib (PLX3397) for the duration of disease. Although we observed an interferon gen, signature in addition to downregulated neuritogenic and synaptic gene pathways with disease, overt inflammation was not eviden by microglial morphology or cytokine transcript levels in R6/2 mice. Nonetheless, CSF1Ri-induced microglial elimination reduced or prevented disease-related grip strength and object recognition deficits, mHTT accumulation, astrogliosis, and striatal volum loss, the latter of which was not associated with reductions in cell number but with the extracellular accto sulphate protroglycans (CSPGs)-a primary component of glial scars. A concurrent loss of proteoglycan nets was also evident in R6/2 mice, and microglial elimination not only prevented this but also strikingly increased perinettrc nets in the brains of naive littermates, suggesting a new role for microglia as homeostatic regulators of perineuronal perineurcrncll net forrllatior and integriry.