Abstract
Spinal muscular atrophy (SMA) is usually considered a lower motor neuron disease; however, growing evidence from both experimental models and clinical studies indicates that SMN deficiency affects the whole CNS, beyond the spinal and brainstem motor system. Here, we investigated the temporal progression and selective vulnerability of cortical projection neurons in the SMNΔ7 mouse model at early (P5) and late (P11) symptomatic stages. Combining subtype-specific immunohistochemistry, DiI tracing associated with morphometric reconstruction, and dendritic spine analysis, we identified stage- and subtype-dependent cortical alterations. At P11, corticospinal and infragranular callosal projection neurons were selectively reduced in number and showed marked dendritic remodeling and altered excitatory synaptic organization, whereas corticothalamic neurons and supragranular SATB2-positive populations were comparatively preserved. Notably, cortical abnormalities were already detectable at P5, before overt neuronal loss: indeed, corticospinal neurons exhibited reduced soma size and dendritic complexity, while dendritic spine density remained preserved, but spine morphology was shifted toward immature phenotypes. These early maturation defects persisted during disease progression and preceded the reduction in spine density observed at P11. Together, our findings identify cortical projection neurons as selectively vulnerable to constitutive SMN deficiency and suggest that impaired neuronal and synaptic maturation represents an early feature of cortical pathology preceding subtype-specific neurodegeneration. These results expand the pathophysiological spectrum of SMA beyond lower motor neurons and highlight early brain alterations as a potential component of disease progression.