Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease.
Huntington's disease is associated with a reactive microglial response and consequent inflammation. To address the role 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 1 receptor inhibition (CSF1Ri) with pexidartinib (PLX3397) for the duration of disease. Although we observed an interferon gene signature in addition to downregulated neuritogenic and synaptic gene pathways with disease, overt inflammation was not evident 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 volume loss, the latter of which was not associated with reductions in cell number but with the extracellular accumulation of chondroitin sulphate proteoglycans (CSPGs)-a primary component of glial scars. A concurrent loss of proteoglycan-containing perineuronal nets was also evident in R6/2 mice, and microglial elimination not only prevented this but also strikingly increased perineuronal nets in the brains of naïve littermates, suggesting a new role for microglia as homeostatic regulators of perineuronal net formation and integrity.
['Crapser|Joshua D|JD|', 'Ochaba|Joseph|J|', 'Soni|Neelakshi|N|', 'Reidling|Jack C|JC|', 'Thompson|Leslie M|LM|', 'Green|Kim N|KN|']
D000631:Aminopyridines D000818:Animals D001253:Astrocytes D011508:Chondroitin Sulfate Proteoglycans D016207:Cytokines D004195:Disease Models, Animal D015536:Down-Regulation D005109:Extracellular Matrix D018737:Hand Strength D006801:Humans D000071058:Huntingtin Protein D006816:Huntington Disease D007249:Inflammation D051379:Mice D008822:Mice, Transgenic D017628:Microglia D017072:Neostriatum D016501:Neurites D011758:Pyrroles D012333:RNA, Messenger D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor D021641:Recognition, Psychology D013569:Synapses D059467:Transcriptome
extracellular matrix Huntington's disease microglia perineuronal nets CSF1R