Selective vulnerability of spinal and cortical motor neuron subpopulations in delta7 SMA mice

Abstract

Loss of the survival motor neuron gene (SMN1) is responsible for spinal muscular atrophy (SMA), the most commoninherited cause of infant mortality. Even though the SMA phenotype is traditionally considered as related to spinalmotor neuron loss, it remains debated whether the specific targeting of motor neurons could represent the best therapeutic option for the disease. We here investigated, using stereological quantification methods, the spinal cord and cerebral motor cortex of Δ7 SMA mice during development, to verify extent and selectivity of motor neuron loss. We found progressive post-natal loss of spinal motor neurons, already at pre-symptomatic stages, and a higher vulnerability of motor neurons innervating proximal and axial muscles. Larger motor neurons decreased in the course of disease, either for selective loss or specific developmental impairment. We also found a selective reduction of layer V pyramidal neurons associated with layer V gliosis in the cerebral motor cortex. Our data indicate that in the Δ7 SMA model SMN loss is critical for the spinal cord, particularly for specific motor neuron pools. Neuronal loss, however, is not selective for lower motor neurons. These data further suggest that SMA pathogenesis is likely morecomplex than previously anticipated. The better knowledge of SMA models might be instrumental in shaping bettertherapeutic options for affected patients. © 2013 d'Errico et al.