NPC1 deficiency impairs cerebellar postnatal development of microglia and climbing fiber refinement in a mouse model of Niemann-Pick Type C disease

Abstract

Little is known about the effects of NPC1 deficiency in brain development and if they contribute to neurodegeneration in Niemann-Pick Type C disease. Since cerebellar Purkinje cells die early and to a higher extent in NPC, here we analyzed the effect of NPC1 deficiency in microglia and climbing fiber synaptic refinement during cerebellar postnatal development using the Npc1nmf164 mouse. Our analysis revealed that NPC1 deficiency leads to early phenotypic changes in microglia that are not associated with an innate immune response. However, the lack of NPC1 in Npc1nmf164 mice significantly affected the early development of microglia by delaying the radial migration, increasing the proliferation and impairing the differentiation of microglia precursor cells during postnatal development. Additionally, increased phagocytic activity of differentiating microglia was found at the end of the second postnatal week in Npc1nmf164 mice. Moreover, significant Climbing-fiber (CF) synaptic refinement deficits along with an increased engulfment of CF synaptic elements by microglia were found in Npc1nmf164 mice, suggesting that profound developmental defects in microglia and synaptic connectivity precede and predispose Purkinje cells to early neurodegeneration in NPC.