Investigating Cerebellar Abnormalities in a mouse model of lysosomal lipid storage disease: Implication for Social Behavior

The cerebellum is a versatile brain region that regulates various motor/non-motor behaviors. Thus, impairments in its architecture and circuitry lead to a wide range of neurodevelopmental/neuropsychiatric disorders. During postnatal development, the cerebellum undergoes changes in its cellular arrangement, guided by the Brain-derived Neurotrophic Factor (BDNF), which plays a role in appropriate development, synaptogenesis, and maintenance of cerebellar connectivity. In Niemann-Pick C1 disease (NPC1), a rare lysosomal lipid storage disease, we have previously shown that a decline in Sonic hedgehog (Shh) and BDNF expression in the first weeks of postnatal development disrupts cerebellar granule cell (GC) migration and maturation, influencing the final cerebellar cytoarchitecture. In Npc1 mice, through immunohistochemistry/ Neurolucida analysis at various stages of early postnatal life, we observed a significant decrease in the amount, size and tortuosity of glomeruli, the main synaptic contact between GC dendrites and axons of mossy fibers. These results prompted us to investigate the presence of functional abnormalities in mature glutamatergic synapses. Therefore, by subcellular protein fractionation, we examined the expression levels of specific presynaptic (Syntaxin 1A, VAMP2, SNAP-25) and postsynaptic (Drebrin, Shank3) proteins during different stages of postnatal development, finding a general SNAP-25 deficiency in Npc1 mice compared to wild type (wt) mice. Furthermore, through Golgi-Cox staining analysis, we characterized the density and morphology of GC dendritic spines in the internal granular layer, both in wt and mutant mice, to identify abnormalities in synapse maturation and pruning processes, during critical stages of cerebellar development. Finally, Npc1 male mice showed no preference for social/nonsocial cues in a typical task used to study autistic-like behavior, consistent with studies indicating reduced levels of cerebellar BDNF in autistic patients.