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Motor neuron rescue in spinal muscular atrophy mice demonstrates that sensory-motor defects are a consequence, not a cause, of motor neuron dysfunction.

The loss of motor neurons (MNs) is a hallmark of the neuromuscular disease spinal muscular atrophy (SMA); however, it is unclear whether this phenotype autonomously originates within the MN. To address this question, we developed an inducible mouse model of severe SMA that has perinatal lethality, decreased motor function, motor unit pathology, and hyperexcitable MNs. Using an Hb9-Cre allele, we increased Smn levels autonomously within MNs and demonstrate that MN rescue significantly improves all phenotypes and pathologies commonly described in SMA mice. MN rescue also corrects hyperexcitability in SMA motor neurons and prevents sensory-motor synaptic stripping. Survival in MN-rescued SMA mice is extended by only 5 d, due in part to failed autonomic innervation of the heart. Collectively, this work demonstrates that the SMA phenotype autonomously originates in MNs and that sensory-motor synapse loss is a consequence, not a cause, of MN dysfunction.

Pubmed ID: 22423102

Authors

  • Gogliotti RG
  • Quinlan KA
  • Barlow CB
  • Heier CR
  • Heckman CJ
  • Didonato CJ

Journal

The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

March 14, 2012

Associated Grants

  • Agency: PHS HHS, Id: 1R0IN5060926
  • Agency: NINDS NIH HHS, Id: 3R01NS060926-02S3
  • Agency: NINDS NIH HHS, Id: NS034382
  • Agency: NINDS NIH HHS, Id: NS054850
  • Agency: NINDS NIH HHS, Id: NS071951
  • Agency: NINDS NIH HHS, Id: R01 NS060926
  • Agency: NINDS NIH HHS, Id: R01 NS060926-02S3
  • Agency: NINDS NIH HHS, Id: R01 NS060926-04
  • Agency: NIA NIH HHS, Id: T32 AG000260
  • Agency: NIMH NIH HHS, Id: T32 MH065215

Mesh Terms

  • Animals
  • Animals, Newborn
  • Female
  • Male
  • Mice
  • Mice, Transgenic
  • Motor Neurons
  • Muscular Atrophy, Spinal
  • Neuromuscular Junction
  • Sensory Receptor Cells