A mild mouse model of SMA, termed Smn^2B/-;SMN2^+/-, was generated by crossing Smn^-/-;SMN2^+/+ and Smn^2B/2B mice. This new model was characterized using behavioral testing, histology, western blot, muscle-nerve electrophysiology as well as ultrasonography to study classical SMA features and extra-neuronal involvement.

The Smn^2B/-;SMN2^+/-mice have normal survival, but display an early histological evidence of central nucleation, a sustained motor weakness, a late-onset motor neuron loss and skeletal muscle atrophy. They show electrophysiological evidence of denervation and neuronal/NMJ transmission defects that are more prominent in male mice. Intrinsic contractile and relaxation muscle defects were also identified. There was an absence of extra-neuronal pathology.

The Smn^2B/-;SMN2^+/-mouse provides a mild model of SMA, displaying hallmark features of motor neuron loss, denervation and muscle atrophy. Interestingly, it has already revealed early histological changes in the muscle and a gender difference. The use of this model will allow for the understanding of the most susceptible pathogenic molecular changes in motor neurons and muscles, investigation of the effects of SMN depletion in aging, sex differences and most importantly will provide guidance for the currently aging SMA patients treated with the recently approved genetic therapies.