Cortical projection neurons exhibit early maturation defects and selective degeneration in a mouse model of spinal muscular atrophy
Year: 2026
Type: preprint
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. Graphical Abstract Cortical projection neuron vulnerability and early maturation defects in SMA Schematic summary of cortical alterations in SMNΔ7 mice. Early structural and synaptic maturation defects are already present in corticospinal neurons at P5 despite preserved projection neuron populations, whereas by P11 these abnormalities are accompanied by reduced spine density and selective degeneration of vulnerable layer V projection neurons (corticospinal and corticocortical). These findings suggest that postnatal developmental defects in neuronal and synaptic maturation represent an early marker of cortical vulnerability to SMN deficiency, preceding the subtype-specific neurodegeneration observed at later disease stages. Created with BioRender.com.
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: Università degli Studi di Torino
OpenAlex ID: W7221452776