Abstract
Spinal muscular atrophy (SMA) is a major genetic cause of death in childhood characterized by marked muscle weakness. To investigate mechanisms underlying motor impairment in SMA, we examined the spinal and neuromuscular circuitry governing hindlimb ambulatory behavior in SMA model mice (SMNΔ7). In the neuromuscular circuitry, we found that nearly all neuromuscular junctions (NMJs) in hindlimb muscles of SMNΔ7 mice remained fully innervated at the disease end stage and were capable of eliciting muscle contraction, despite a modest reduction in quantal content. In the spinal circuitry, we observed a ∼28% loss of synapses onto spinal motoneurons in the lateral column of lumbar segments 3–5, and a significant reduction in proprioceptive sensory neurons, which may contribute to the 50% reduction in vesicular glutamate transporter 1(VGLUT1)-positive synapses onto SMNΔ7 motoneurons. In addition, there was an increase in the association of activated microglia with SMNΔ7 motoneurons. Together, our results present a novel concept that synaptic defects occur at multiple levels of the spinal and neuromuscular circuitry in SMNΔ7 mice, and that proprioceptive spinal synapses could be a potential target for SMA therapy.
Highlights
Spinal muscular atrophy (SMA), a leading genetic cause of infant mortality, is an autosomal recessive motoneuron disease characterized by spinal motoneuron loss, muscle atrophy and motor impairment [1,2]
This disease is caused by deletion or mutation of the survival of motor neuron 1 (SMN1) gene and low expression of the SMN protein derived from the closely-related SMN2 gene, and as such the disease severity is determined by SMN2 gene copy numbers
Throughout disease progression, we found that most neuromuscular junctions (NMJs) in the extensor digitorum longus (EDL) muscle of SMND7 mice, as in non-SMA control littermates, were fully innervated (Fig. 1A and 1B)
Summary
Spinal muscular atrophy (SMA), a leading genetic cause of infant mortality, is an autosomal recessive motoneuron disease characterized by spinal motoneuron loss, muscle atrophy and motor impairment [1,2]. This disease is caused by deletion or mutation of the survival of motor neuron 1 (SMN1) gene and low expression of the SMN protein derived from the closely-related SMN2 gene, and as such the disease severity is determined by SMN2 gene copy numbers. No denervation is observed in a wide range of major limb muscles [6,9] It remains intriguing why the ambulatory function is impaired. Further functional analyses of the NMJ and muscle contraction in SMND7 mice would resolve the role of NMJs in muscle weakness
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