Alteration of cholinergic pathway in the enteric nervous system of a mouse model of Rett syndrome
Abstract
Background and aims: Rett syndrome (RTT) is a severe neurological disorder caused by pathogenic variants in the MECP2 gene associated with gastrointestinal (GI) motility disorders strongly impacting patients' quality of life. Intestinal motility relies on coordinated neuronal activity in the enteric nervous system (ENS) where MECP2 is highly expressed. Here, we sought to determine whether cholinergic-mediated excitatory neuromuscular transmission could be affected in the ENS of a RTT mouse model and the functional consequences on intestinal motility. Methods: In this study, 55 days-old wild type (WT) and Mecp2-knock-out (KO) mice were used. After confirming the increase in GI transit time in Mecp2-KO mice in vivo, intestinal mechanical activity was assessed in vitro by evaluating contractile responses of small intestinal muscle to electrical field stimulation (EFS) of the ENS. The function of the cholinergic pathway was evaluated using gene expression, protein, and enzymatic activity quantifications of different factors of the acetylcholine (ACh) metabolism. Results: Our in vivo results confirm that the slowed GI transit previously identified in RTT patients and in the mouse model. In vitro, successive EFS lead to a progressive and rapid decrease in the amplitude of cholinergic contractions in Mecp2-KO mice contrary to WT mice. Levels of ACh are decreased in the ENS of Mecp2-KO mice (-47%, P-value<0.01) due to decreased activity of the synthesizing enzyme choline-acetyltransferase (-39%, Pvalue = 0.04). In addition to the deficit of ACh, we found that both nicotinic and muscarinic cholinergic receptors are also significantly impacted. Conclusion: This is the first report of a major dysfunction of the enteric cholinergic pathway in a mouse model of RTT supporting its direct involvement in GI disorders in this disease. We propose that the rhythmic GI contractions occurring during fed conditions may cause a rapid depletion of the stock of enteric ACh that could largely depress the propulsive efficiency of, or even suppress, peristalsis during digestion.
Related
- Alteration of empathy-related behaviors in two strains of mice expressing mutations of the α5 cholinergic nicotinic receptor subunit
- Anatomical and functional organisation of the cholinergic nervous system in the tunicate Botryllus schlosseri
- Maladaptive sensory coding in the enteric nervous system playing a role in gastrointestinal disorders.
- Immunoregulatory roles of the enteric nervous system in esophageal motility control: mechanisms, advances, and therapeutic potential
- A specific basal forebrain–medial prefrontal cholinergic pathway improves attentional control in male mice
BibTeX
@article{borloz2026alteration,
title = {{Alteration of cholinergic pathway in the enteric nervous system of a mouse model of Rett syndrome}},
author = {Emilie Borloz and Camille de Combarieu and Léna Bourcin and Marie-Solenne Felix and Camille Fulachier and Bruno Mazet and Jean-Christophe Roux},
journal = {Neurobiology of Disease},
year = {2026},
month = sep,
doi = {10.1016/j.nbd.2026.107597},
url = {https://hal.science/hal-05744974v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Alteration of cholinergic pathway in the enteric nervous system of a mouse model of Rett syndrome
AU - Emilie Borloz
AU - Camille de Combarieu
AU - Léna Bourcin
AU - Marie-Solenne Felix
AU - Camille Fulachier
AU - Bruno Mazet
AU - Jean-Christophe Roux
PY - 2026
DA - 2026/09/10
JO - Neurobiology of Disease
DO - 10.1016/j.nbd.2026.107597
UR - https://hal.science/hal-05744974v1
AB - Background and aims: Rett syndrome (RTT) is a severe neurological disorder caused by pathogenic variants in the MECP2 gene associated with gastrointestinal (GI) motility disorders strongly impacting patients' quality of life. Intestinal motility relies on coordinated neuronal activity in the enteric nervous system (ENS) where MECP2 is highly expressed. Here, we sought to determine whether cholinergic-mediated excitatory neuromuscular transmission could be affected in the ENS of a RTT mouse model and the functional consequences on intestinal motility. Methods: In this study, 55 days-old wild type (WT) and Mecp2-knock-out (KO) mice were used. After confirming the increase in GI transit time in Mecp2-KO mice in vivo, intestinal mechanical activity was assessed in vitro by evaluating contractile responses of small intestinal muscle to electrical field stimulation (EFS) of the ENS. The function of the cholinergic pathway was evaluated using gene expression, protein, and enzymatic activity quantifications of different factors of the acetylcholine (ACh) metabolism. Results: Our in vivo results confirm that the slowed GI transit previously identified in RTT patients and in the mouse model. In vitro, successive EFS lead to a progressive and rapid decrease in the amplitude of cholinergic contractions in Mecp2-KO mice contrary to WT mice. Levels of ACh are decreased in the ENS of Mecp2-KO mice (-47%, P-value<0.01) due to decreased activity of the synthesizing enzyme choline-acetyltransferase (-39%, Pvalue = 0.04). In addition to the deficit of ACh, we found that both nicotinic and muscarinic cholinergic receptors are also significantly impacted. Conclusion: This is the first report of a major dysfunction of the enteric cholinergic pathway in a mouse model of RTT supporting its direct involvement in GI disorders in this disease. We propose that the rhythmic GI contractions occurring during fed conditions may cause a rapid depletion of the stock of enteric ACh that could largely depress the propulsive efficiency of, or even suppress, peristalsis during digestion.
SN - 0969-9961
SN - 1095-953X
ER -