Cerebellar structural, astrocytic, and neuronal abnormalities in the SMNΔ7 mouse model of spinal muscular atrophy

Spinalmuscular atrophy (SMA) is a neuromuscular disease that affects as many as 1 in 6000 individuals at birth, making it the leading genetic cause of infant mortality. A growing number of studies indicate that SMA is a multi‐system disease. The cerebellum has received little attention even though it plays an important role in motor function and widespread pathology has been reported in the cerebella of SMA patients. In this study, we assessed SMA pathology in the cerebellum using structural and diffusion magnetic resonance imaging, immunohistochemistry, and electrophysiology with the SMNΔ7 mouse model. We found a significant disproportionate loss in cerebellar volume, decrease in afferent cerebellar tracts, selective lobule‐specific degeneration of Purkinje cells, abnormal lobule foliation and astrocyte integrity, and a decrease in spontaneous firing of cerebellar output neurons in the SMA mice compared to controls. Our data suggest that defects in cerebellar structure and function due to decreased survival motor neuron (SMN) levels impair the functional cerebellar output affecting motor control, and that cerebellar pathology should be addressed to achieve comprehensive treatment and therapy for SMA patients. Our study showed structural and functional abnormalities in the cerebellum of spinal muscular atrophy (SMA) mice. SMA cerebella display lobule‐specific structural (red, darker shade = greater effect) and Purkinje cell degeneration (PC, green). Granule cell proliferation and migration through the molecular layer (ML) is abnormal in anterior and posterior lobules (blue); the tract formation of inferior and middle peduncles (pink, lighter shade = less tract formation) and functional output (purple) of deep cerebellar nuclei (DCN) neurons are decreased in SMA cerebella.