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

Brain. 2020 Jan 1;143(1):266-288. doi: 10.1093/brain/awz363.


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.

Keywords: CSF1R; Huntington's disease; extracellular matrix; microglia; perineuronal nets.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aminopyridines / pharmacology*
  • Animals
  • Astrocytes / drug effects
  • Chondroitin Sulfate Proteoglycans / drug effects
  • Chondroitin Sulfate Proteoglycans / metabolism
  • Cytokines / drug effects
  • Cytokines / genetics
  • Disease Models, Animal
  • Down-Regulation
  • Extracellular Matrix / drug effects*
  • Extracellular Matrix / metabolism
  • Hand Strength
  • Humans
  • Huntingtin Protein / drug effects*
  • Huntingtin Protein / genetics
  • Huntingtin Protein / metabolism
  • Huntington Disease / genetics
  • Huntington Disease / metabolism*
  • Huntington Disease / pathology
  • Huntington Disease / physiopathology
  • Inflammation
  • Mice
  • Mice, Transgenic
  • Microglia / drug effects*
  • Neostriatum / drug effects*
  • Neostriatum / pathology
  • Neurites / drug effects
  • Pyrroles / pharmacology*
  • RNA, Messenger / metabolism
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / antagonists & inhibitors
  • Recognition, Psychology / drug effects*
  • Synapses / drug effects
  • Transcriptome


  • Aminopyridines
  • Chondroitin Sulfate Proteoglycans
  • Csf1r protein, mouse
  • Cytokines
  • HTT protein, human
  • Huntingtin Protein
  • Pyrroles
  • RNA, Messenger
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • pexidartinib