Cerebellar defects are a primary pathology in mouse models of spinal muscular atrophy.

Spinal muscular atrophy (SMA), a leading genetic cause of infant mortality worldwide, is caused by reduced levels of the ubiquitous survival motor neuron (SMN) protein in SMA patients. Despite significant advancement in recent research and clinical treatments, the cellular pathologies that underlie SMA disease manifestations are not well characterized beyond those of spinal motor neurons (MNs). We previously reported cerebellar abnormalities in an SMA mouse model at the late stage of the disease, including volumetric deficits and lobule-selective structural changes with Purkinje cell degeneration, with colocalized astrocytic reactivity. However, when these cerebellar defects arise and whether they are a consequence of MN degeneration remain unknown. We used magnetic resonance imaging, immunohistochemistry, and electrophysiology to characterize cerebellar pathology in early-stage symptomatic SMNΔ7 mice and late-stage SMA mice with transgenic rescue of SMN in MNs. We found disproportionate structural and lobule-specific surface area deficits, as well as abnormal functional properties in the cerebella of early symptomatic SMA mice, suggesting that cerebellar pathologies may be a primary contributor to murine SMA phenotypes. Moreover, cerebellar pathologies were not ameliorated in SMA mice with MN rescue, suggesting that cerebellar neurons are independently vulnerable to reduced SMN expression. Overall, our study shows that cerebellar defects are a primary pathology in SMA mouse models and that therapies targeting cerebellar neurons in SMA patients may be needed for optimal treatment outcomes.