Enteric glutamatergic interneurons regulate intestinal motility

Ryan Hamnett¹, Jacqueline L Bendrick², Zinnia Saha³, Keiramarie Robertson², Cheyanne M Lewis², Jack H Marciano², Eric Tianjiao Zhao⁴, Julia A Kaltschmidt⁵

Affiliations

¹ Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA. Electronic address: rhamnett@stanford.edu.
² Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA; Stanford Neurosciences Interdepartmental Program, Stanford University, Stanford, CA 94305, USA.
³ Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA.
⁴ Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA; Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.
⁵ Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA. Electronic address: jukalts@stanford.edu.

PMID: 39983724
PMCID: PMC11968238 (available on 2026-04-02)
DOI: 10.1016/j.neuron.2025.01.014

Enteric glutamatergic interneurons regulate intestinal motility

Ryan Hamnett et al. Neuron. 2025.

. 2025 Apr 2;113(7):1019-1035.e6.

doi: 10.1016/j.neuron.2025.01.014. Epub 2025 Feb 20.

Authors

Ryan Hamnett¹, Jacqueline L Bendrick², Zinnia Saha³, Keiramarie Robertson², Cheyanne M Lewis², Jack H Marciano², Eric Tianjiao Zhao⁴, Julia A Kaltschmidt⁵

Affiliations

¹ Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA. Electronic address: rhamnett@stanford.edu.
² Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA; Stanford Neurosciences Interdepartmental Program, Stanford University, Stanford, CA 94305, USA.
³ Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA.
⁴ Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA; Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA.
⁵ Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA. Electronic address: jukalts@stanford.edu.

PMID: 39983724
PMCID: PMC11968238 (available on 2026-04-02)
DOI: 10.1016/j.neuron.2025.01.014

Abstract

The enteric nervous system (ENS) controls digestion autonomously via a complex neural network within the gut wall. Enteric neurons expressing glutamate have been identified by transcriptomic studies as a distinct subpopulation, and glutamate can affect intestinal motility by modulating enteric neuron activity. However, the nature of glutamatergic neurons, their position within the ENS circuit, and their function in regulating gut motility are unknown. We identify glutamatergic neurons as longitudinally projecting descending interneurons in the small intestine and colon and as a novel class of circumferential neurons only in the colon. Both populations make synaptic contact with diverse neuronal subtypes and signal with multiple neurotransmitters and neuropeptides in addition to glutamate, including acetylcholine and enkephalin. Knocking out the glutamate transporter VGLUT2 from enkephalin neurons disrupts gastrointestinal transit, while ex vivo optogenetic stimulation of glutamatergic neurons initiates colonic propulsive motility. Our results posit glutamatergic neurons as key interneurons that regulate intestinal motility.

Keywords: enteric nervous system; glutamate; interneurons; mouse; optogenetics; synapses.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

References

1. Furness JB (2012). The enteric nervous system and neurogastroenterology. Nature Reviews Gastroenterology and Hepatology 9, 286–294. 10.1038/nrgastro.2012.32. - DOI - PubMed
1. Fung C, and Vanden Berghe P (2020). Functional circuits and signal processing in the enteric nervous system. Cellular and Molecular Life Sciences 77, 4505–4522. 10.1007/s00018-020-03543-6. - DOI - PMC - PubMed
1. Rao M, and Gershon MD (2016). The bowel and beyond: The enteric nervous system in neurological disorders. Nature Reviews Gastroenterology and Hepatology 13, 517–528. 10.1038/nrgastro.2016.107. - DOI - PMC - PubMed
1. Spencer NJ, and Hu H (2020). Enteric nervous system: sensory transduction, neural circuits and gastrointestinal motility. Nature Reviews Gastroenterology & Hepatology 2020 17, 338–351. 10.1038/s41575-020-0271-2. - DOI - PMC - PubMed
1. Drokhlyansky E, Smillie CS, Van Wittenberghe N, Ericsson M, Griffin GK, Eraslan G, Dionne D, Cuoco MS, Goder-Reiser MN, Sharova T, et al. (2020). The Human and Mouse Enteric Nervous System at Single-Cell Resolution. Cell 182, 1606–1622.e23. 10.1016/j.cell.2020.08.003. - DOI - PMC - PubMed

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Enteric glutamatergic interneurons regulate intestinal motility

Affiliations

Enteric glutamatergic interneurons regulate intestinal motility

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases