SMN deficiency disrupts gastrointestinal and enteric nervous system function in mice

Area of Science:

• Neuroscience
• Gastroenterology
• Genetics

Background:

• Spinal Muscular Atrophy (SMA) patients exhibit gastrointestinal (GI) dysfunctions, including reflux, constipation, and delayed gastric emptying.
• The precise mechanisms underlying these GI complications in SMA remain unclear.

Purpose of the Study:

• To investigate whether functional GI complications in SMA are a direct result of survival motor neuron (Smn) protein deficiency.
• To determine the impact of Smn deficiency on the enteric nervous system (ENS) and gut motility.

Main Methods:

• Utilized two mouse models of SMA exhibiting Smn deficiency.
• Assessed GI function, including motility and transit, in SMA mice compared to controls.
• Examined ENS signaling and smooth muscle contractility in distal colon segments using electrical field stimulation (EFS).

Main Results:

• Smn deficiency in mice caused constipation, delayed gastric emptying, slow intestinal transit, and reduced colonic motility, despite normal food/water intake and activity.
• No gross anatomical or histopathological abnormalities were observed in the GI tract.
• Smn deficiency disrupted ENS signaling to colonic smooth muscle, leading to hyperexcitability and increased contractility (up to 10-fold) upon EFS, without enteric neuron loss.

Conclusions:

• Smn deficiency directly impacts the intrinsic neural control of gut function mediated by the ENS.
• Altered ENS signaling and hyperexcitability, rather than neuron loss, underlie the GI symptoms observed in SMA mouse models.
• These findings suggest ENS cells are susceptible to Smn deficiency, potentially explaining the GI symptoms in SMA patients.