Altered cerebellar granule cell differentiation and synapse maturation in a mouse model of a lysosomal lipid storage disease.

The rare Niemann-Pick type C1 (NPC1) disease is a lysosomal lipid storage disorder, caused by mutations in the Npc1 gene. Since the encoded protein mediates the outflow of cholesterol from endosomal-lysosomal compartments, these mutations cause intracellular cholesterol and other lipids overload, leading to neurodegeneration, neurovisceral symptoms and early death. Both NPC1 patients and animal models develop neurological manifestations and ataxia due to Purkinje cell loss. We demonstrated a reduced proliferation of cerebellar granule neurons that influences the size of all cerebellar lobules of NPC1-deficient mice, caused by a significant decrease in the availability of Shh signaling, at the level of the primary cilium. Multiple extrinsic signals, such as Brain-Derived Neurotrophic Factor (BDNF), are needed to support post-natal cerebellar developmental processes, including migration and differentiation of granule precursors as well as connectivity within the cerebellar cortex. For instance, mossy fiber axons represent one of the main excitatory inputs to the internal granule layer and are the primary source of BDNF. Therefore, we wondered if BDNF-mediated signaling was involved in impaired cerebellar morphogenesis in hypomorphic Npc1nmf164/nmf164 mice, characterized by a slow progression of the disease. By immunohistochemistry/biochemical and morphological approaches on PN11-PN30 Npc1nmf164/nmf164 mice, we observed a strong downregulation of BDNF and its receptor, abnormal differentiation of granule neurons and alterations in the structure/connectivity of mossy fibers. In line with previous studies that demonstrated reduced cerebellar BDNF levels in autistic patients, male Npc1nmf164/nmf164 mice showed no preference for social/nonsocial stimulus in a typical task exploited to investigate autistic-like behaviour .