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SMN deficiency disrupts gastrointestinal and enteric nervous system function in mice.

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      Abstract

      The 2007 Consensus Statement for Standard of Care in Spinal Muscular Atrophy (SMA) notes that patients suffer from gastroesophageal reflux, constipation and delayed gastric emptying. We used two mouse models of SMA to determine whether functional GI complications are a direct consequence of or are secondary to survival motor neuron (Smn) deficiency. Our results show that despite normal activity levels and food and water intake, Smn deficiency caused constipation, delayed gastric emptying, slow intestinal transit and reduced colonic motility without gross anatomical or histopathological abnormalities. These changes indicate alterations to the intrinsic neural control of gut functions mediated by the enteric nervous system (ENS). Indeed, Smn deficiency led to disrupted ENS signaling to the smooth muscle of the colon but did not cause enteric neuron loss. High-frequency electrical field stimulation (EFS) of distal colon segments produced up to a 10-fold greater contractile response in Smn deficient tissues. EFS responses were not corrected by the addition of a neuronal nitric oxide synthase inhibitor indicating that the increased contractility was due to hyperexcitability and not disinhibition of the circuitry. The GI symptoms observed in mice are similar to those reported in SMA patients. Together these data suggest that ENS cells are susceptible to Smn deficiency and may underlie the patient GI symptoms.

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      Affiliations
      [1 ] Department of Neuroscience, Wexner Medical Center.
      [2 ] Department of Molecular & Cellular Biochemistry, Wexner Medical Center and.
      [3 ] Department of Physiology, Neuroscience Program, Michigan State University, East Lansing, MI 48824, USA and.
      [4 ] Division of Pediatric Gastroenterology, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
      [5 ] Department of Anesthesiology, The Ohio State University, Columbus, OH 43210, USA.
      [6 ] Department of Neuroscience, Wexner Medical Center, kevin.foust@osumc.edu.
      Journal
      Hum. Mol. Genet.
      Human molecular genetics
      Oxford University Press (OUP)
      1460-2083
      0964-6906
      Jul 01 2015
      : 24
      : 13
      25859009 ddv127 10.1093/hmg/ddv127 4542833

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