Impaired cerebellar development/function in a mouse model of Niemann-Pick C1

The cerebellum is a multifunctional brain region that controls various motor and non-motor behaviors. Thus, impairments in cerebellar architecture and circuitry lead to a wide range of neurodevelopmental/neuropsychiatric disorders. During postnatal development, the cerebellum undergoes changes in its cellular organization, controlled by neurotrophic factors, such as BDNF-TrkB signaling that is involved in the proper development, synaptogenesis, and maintenance of cerebellar circuitry. In Niemann-Pick C1 (NPC1) disease, a rare lipid-storage disorder, we have previously demonstrated that a reduction in the Shh and BDNF expression in the first weeks of postnatal development disturbs the proliferation and migration of cerebellar granule cells (GCs) influencing the final cerebellar cytoarchitecture. As for the GCs, their complete differentiation into the inner granular layer by connecting, via their dendrites, with mossy fiber axons and establishing the major synaptic complex, known as the glomerulus. In Npc1 mice, by immunohistochemistry and Neurolucida analysis, we observed a significant reduction in the number, area and tortuosity of glomeruli at different stages of early postnatal life. These results led us to investigate the presence of functional defects at the level of mature glutamatergic synapses. Therefore, by subcellular protein fractionation, we investigated the expression levels of specific pre-synaptic (Syntaxin 1A, VAMP2, SNAP-25) and postsynaptic (Drebrin, Shank3) proteins during different stages of postnatal cerebellar development and revealed a general SNAP-25 deficiency in Npc1 mice versus wt. Furthermore, by Golgi-Cox staining analysis, we also characterized the density/morphology of GC dendritic spines in the IGL, both in wt and mutant mice, to identify defects in synapse maturation and pruning processes during the key steps of cerebellar development. Finally, male Npc1 mice showed no preference for social/nonsocial stimulus in a typical task exploited to study autistic-like behaviour, consistent with studies demonstrating reduced levels of cerebellar BDNF in autistic patients.