Reduced cerebellar BDNF availability affects postnatal differentiation and maturation of granule cells in a mouse model of cholesterol dyshomeostasis

Niemann-Pick type C1 (NPC1) disease is a lysosomal lipid storage disorder due to mutations in the NPC1 gene resulting in the accumulation of cholesterol within the endosomal/lysosomal compartments. The prominent feature of the disorder is the progressive Purkinje cell degeneration leading to ataxia.In a mouse model of NPC1 disease, we have previously demonstrated that impaired Sonic hedgehog signaling causes defec-tive proliferation of granule cells (GCs) and abnormal cerebellar morphogenesis. Studies conducted on cortical and hippocampal neurons indicate a functional interaction between Sonic hedgehog and brain-derived neurotrophic factor (BDNF)expression, leading us to hypothesize that BDNF signaling may be altered in Npc1 mutant mice, contributing to the on set of cerebellar alterations present in NPC1 disease before the appearance of signs of ataxia. We characterized the expression/localization patterns of the BDNF and its receptor, tropomyosin-related kinase B (TrkB),in the early postnatal and young adult cerebellum of the Npc1nmf164 mutant mouse strain. In Npc1nmf164 mice, our results show (i) a reduced expression of cerebellar BDNF and pTrkB in the first 2 weeks postpartum, phases in which most GCs complete the proliferative/migrative program and begin differentiation; (ii) an altered subcellular localization of the pTrkB receptor in GCs, both in vivo and in vitro; (iii) reduced chemotactic response to BDNF in GCscultured in vitro, associated with impaired internalization of the activated TrkB receptor; (iv) an overall increase in dendritic branching in mature GCs, resulting in impaired differentiation of the cerebellar glomeruli, the major synaptic complex between GCs and mossy fibers