Selective vulnerability of motor neurons and dissociation of pre- and post-synaptic pathology at the neuromuscular junction in mouse models of spinal muscular atrophy

Hum Mol Genet. 2008 Apr 1;17(7):949-62. doi: 10.1093/hmg/ddm367. Epub 2007 Dec 8.


Proximal spinal muscular atrophy (SMA) is a common autosomal recessive childhood form of motor neuron disease. Previous studies have highlighted nerve- and muscle-specific events in SMA, including atrophy of muscle fibres and post-synaptic motor endplates, loss of lower motor neuron cell bodies and denervation of neuromuscular junctions caused by loss of pre-synaptic inputs. Here we have undertaken a detailed morphological investigation of neuromuscular synaptic pathology in the Smn-/-;SMN2 and Smn-/-;SMN2;Delta7 mouse models of SMA. We show that neuromuscular junctions in the transversus abdominis (TVA), levator auris longus (LAL) and lumbrical muscles were disrupted in both mouse models. Pre-synaptic inputs were lost and abnormal accumulations of neurofilament were present, even in early/mid-symptomatic animals in the most severely affected muscle groups. Neuromuscular pathology was more extensive in the postural TVA muscle compared with the fast-twitch LAL and lumbrical muscles. Pre-synaptic pathology in Smn-/-;SMN2;Delta7 mice was reduced compared with Smn-/-;SMN2 mice at late-symptomatic time-points, although post-synaptic pathology was equally severe. We demonstrate that shrinkage of motor endplates does not correlate with loss of motor nerve terminals, signifying that one can occur in the absence of the other. We also demonstrate selective vulnerability of a subpopulation of motor neurons in the caudal muscle band of the LAL. Paralysis with botulinum toxin resulted in less terminal sprouting and ectopic synapse formation in the caudal band compared with the rostral band, suggesting that motor units conforming to a Fast Synapsing (FaSyn) phenotype are likely to be more vulnerable than those with a Delayed Synapsing (DeSyn) phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Botulinum Toxins, Type A / physiology
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / physiology
  • Disease Models, Animal
  • Humans
  • In Vitro Techniques
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Electron
  • Microscopy, Fluorescence
  • Motor Neurons / pathology
  • Motor Neurons / physiology*
  • Muscle Fibers, Skeletal / physiology
  • Muscle, Skeletal / pathology
  • Muscular Atrophy, Spinal / physiopathology*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / physiology
  • Neurofilament Proteins / metabolism
  • Neuromuscular Junction / pathology
  • Neuromuscular Junction / physiopathology*
  • Paralysis / physiopathology
  • Phenotype
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / physiology
  • SMN Complex Proteins
  • Survival of Motor Neuron 2 Protein


  • Cyclic AMP Response Element-Binding Protein
  • Nerve Tissue Proteins
  • Neurofilament Proteins
  • RNA-Binding Proteins
  • SMN Complex Proteins
  • SMN2 protein, human
  • Survival of Motor Neuron 2 Protein
  • Botulinum Toxins, Type A