Human Molecular Genetics Advance Access published online on December 8, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm367
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Selective Vulnerability of Motor Neurons and Dissociation of Pre- and Post-Synaptic Pathology at the Neuromuscular Junction in Mouse Models of Spinal Muscular Atrophy
1 Centre for Integrative Physiology, University of Edinburgh Medical School, Edinburgh, EH8 9XD, UK 2 Centre for Neuroscience Research, University of Edinburgh Medical School, Edinburgh, EH8 9XD, UK 3 MRC Functional Genetics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3QX, UK
* Corresponding Author: Dr Thomas H. Gillingwater, Centre for Integrative Physiology, University of Edinburgh Medical School, Edinburgh, EH8 9XD, UK. Email: T.Gillingwater{at}ed.ac.uk, Tel: +44 (0)131 6503724
Received October 30, 2007; Revised December 5, 2007; Accepted December 5, 2007
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;
7 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 to the fast-twitch LAL and lumbrical muscles. Pre-synaptic pathology in Smn-/-;SMN2;7 mice was reduced compared to 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 to 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.
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