Cerebellar BDNF signaling downregulation and autistic-like traits: Insights from a cholesterol storage disorder mouse model

The cerebellum is a multifunctional brain region, controlling various motor and non-motor behaviors. Alterations in its architecture/function contribute to neurodevelopmental disorders, including autism spectrum disorders. In Niemann-Pick C1 (NPC1) disease, a lysosomal lipid accumulation disorder, cerebellar granule cells (GCs) proliferation and migration are impaired, due to reduced levels of Shh and BDNF during early postnatal development, affecting cerebellar cytoarchitecture. Since GCs complete their differentiation in early postnatal life driven by BDNF signaling, establishing synaptic contacts with mossy fibers axons, and creating the major cerebellar synaptic complex known as the glomerulus, we hypothesized the presence of significant synaptic abnormalities in the cerebellum of adult Npc1 mice. Using subcellular protein fractionation and immunofluorescence analysis, we investigated the expression levels of presynaptic (Syntaxin-1A/VAMP2/SNAP25), postsynaptic (Drebrin/Shank3/PSD95/Gephyrin) and synaptic adhesion (Neuroligin 1/2/3) proteins, and we identified a general SNAP25, Shank3 and Neuroligin3 deficiency in Npc1 cerebella. By Golgi-Cox staining analysis during key-stages of cerebellar development (PN11, 30, 60), we found a notable increase in the total number of dendritic spines in Npc1 GCs, particularly in adult males. The increase in both immature and mature spines density suggests a pruning deficiency during cerebellar maturation, causing immature spines to persist well beyond the completion of spinogenesis. Furthermore, the analysis of social behavioral tests revealed autistic-like behavior exclusively in male Npc1 mice. These findings suggest that NPC1 mouse model may provide new insights into the neurobiological mechanisms underlying the autism spectrum disorders, aligning with the altered crosstalk between BDNF/cholesterol and synaptic plasticity already observed in autism.