Molecular and functional diversity of GABA-A receptors in the enteric nervous system of the mouse colon

Mohsen Seifi, James F. Brown, Jeremy Mills, Pradeep Bhandari, Delia Belelli, Jeremy J. Lambert, Uwe Rudolph, Jerome D. Swinny

Research output: Contribution to journalArticle

Abstract

The enteric nervous system (ENS) provides the intrinsic neural control of the gastrointestinal tract (GIT) and regulates virtually all GI functions. Altered neuronal activity within the ENS underlies various GI disorders with stress being a key contributing factor. Thus, elucidating the expression and function of the neurotransmitter systems, which determine neuronal excitability within the ENS, such as the GABA-GABAAreceptor (GABAAR) system, could reveal novel therapeutic targets for such GI disorders. Molecular and functionally diverse GABAARs modulate rapid GABAergic-mediated regulation of neuronal excitability throughout the nervous system. However, the cellular and subcellular GABAAR subunit expression patterns within neurochemically defined cellular circuits of the mouse ENS, together with the functional contribution of GABAAR subtypes to GI contractility remains to be determined. Immunohistochemical analyses revealed that immunoreactivity for the GABAAR gamma (γ) 2 and alphas (α) 1, 2, 3 subunits was located on somatodendritic surfaces of neurochemically distinct myenteric plexus neurons, while being on axonal compartments of submucosal plexus neurons. In contrast, immunoreactivity for the α4-5 subunits was only detected in myenteric plexus neurons. Furthermore, α-γ2 subunit immunoreactivity was located on non-neuronal interstitial cells of Cajal. In organ bath studies, GABAAR subtype-specific ligands had contrasting effects on the force and frequency of spontaneous colonic longitudinal smooth muscle contractions. Finally, enhancement of γ2-GABAAR function with alprazolam reversed the stress-induced increase in the force of spontaneous colonic contractions. The study demonstrates the molecular and functional diversity of the GABAAR system within the mouse colon providing a framework for developing GABAAR-based therapeutics in GI disorders. © 2014 the authors.
Original languageEnglish
Pages (from-to)10361-10378
Number of pages18
JournalJournal of Neuroscience
Volume34
Issue number31
DOIs
Publication statusPublished - 2014

Fingerprint

Neurologic Mutant Mice
Enteric Nervous System
GABA-A Receptors
Colon
Myenteric Plexus
Neurons
Submucous Plexus
Interstitial Cells of Cajal
Alprazolam
Muscle Contraction
Baths
gamma-Aminobutyric Acid
Nervous System
Smooth Muscle
Neurotransmitter Agents
Gastrointestinal Tract
Ligands
Therapeutics

Cite this

Seifi, M., Brown, J. F., Mills, J., Bhandari, P., Belelli, D., Lambert, J. J., ... Swinny, J. D. (2014). Molecular and functional diversity of GABA-A receptors in the enteric nervous system of the mouse colon. Journal of Neuroscience, 34(31), 10361-10378. https://doi.org/10.1523/JNEUROSCI.0441-14.2014
Seifi, Mohsen ; Brown, James F. ; Mills, Jeremy ; Bhandari, Pradeep ; Belelli, Delia ; Lambert, Jeremy J. ; Rudolph, Uwe ; Swinny, Jerome D. / Molecular and functional diversity of GABA-A receptors in the enteric nervous system of the mouse colon. In: Journal of Neuroscience. 2014 ; Vol. 34, No. 31. pp. 10361-10378.
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Seifi, M, Brown, JF, Mills, J, Bhandari, P, Belelli, D, Lambert, JJ, Rudolph, U & Swinny, JD 2014, 'Molecular and functional diversity of GABA-A receptors in the enteric nervous system of the mouse colon' Journal of Neuroscience, vol. 34, no. 31, pp. 10361-10378. https://doi.org/10.1523/JNEUROSCI.0441-14.2014

Molecular and functional diversity of GABA-A receptors in the enteric nervous system of the mouse colon. / Seifi, Mohsen; Brown, James F.; Mills, Jeremy; Bhandari, Pradeep; Belelli, Delia; Lambert, Jeremy J.; Rudolph, Uwe; Swinny, Jerome D.

In: Journal of Neuroscience, Vol. 34, No. 31, 2014, p. 10361-10378.

Research output: Contribution to journalArticle

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