Perinatal high-fat diet alters development of GABAA receptor subunits in dorsal motor nucleus of vagus

Courtney Clyburn, Caitlin A. Howe, Amy Arnold, Charles H. Lang, Renato Alberto Travagli, Kirsteen Browning

Research output: Contribution to journalArticle

Abstract

Perinatal high-fat diet (pHFD) exposure increases the inhibition of dorsal motor nucleus of the vagus (DMV) neurons, potentially contributing to the dysregula-tion of gastric functions. The aim of this study was to test the hypothesis that pHFD increases the inhibition of DMV neurons by disrupting GABAA receptor subunit development. In vivo gastric recordings were made from adult anesthetized Sprague-Dawley rats fed a control or pHFD (14 or 60% kcal from fat, respectively) from embryonic day 13 (E13) to postnatal day 42 (P42), and response to brainstem microinjection of benzodiazepines was assessed. Whole cell patch clamp recordings from DMV neurons assessed the functional expression of GABAA α subunits, whereas mRNA and protein expression were measured via qPCR and Western blotting, respectively. pHFD decreased basal antrum and corpus motility, whereas brainstem microinjection of L838,417 (positive allosteric modulator of α2/3 subunit-containing GABAA receptors) produced a larger decrease in gastric tone and motility. GABAergic miniature inhibitory postsynaptic currents in pHFD DMV neurons were responsive to L838,417 throughout development, unlike control DMV neurons, which were responsive only at early postnatal timepoints. Brainstem mRNA and protein expression of the GABAA α1,2, and3 subunits, however, did not differ between control and pHFD rats. This study suggests that pHFD exposure arrests the development of synaptic GABAA α2/3 receptor subunits on DMV neurons and that functional synaptic expression is maintained into adulthood, although cellular localization may differ. The tonic activation of slower GABAA α2/3 subunit-containing receptors implies that such developmental changes may contribute to the observed decreased gastric motility. NEW & NOTEWORTHY Vagal neurocircuits involved in the control of gastric functions, satiation, and food intake are subject to significant developmental regulation postnatally, with immature GABAA receptors expressing slower α2/3-subunits, whereas mature GABAA receptor express faster α1-subunits. After perinatal high-fat diet exposure, this developmental regulation of dorsal motor nucleus of the vagus (DMV) neurons is disrupted, increasing their tonic GABAergic inhibition, decreasing efferent output, and potentially decreasing gastric motility.

Original languageEnglish (US)
Pages (from-to)G40-G50
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume317
Issue number1
DOIs
StatePublished - Jul 1 2019

Fingerprint

High Fat Diet
GABA-A Receptors
Stomach
Neurons
Brain Stem
Microinjections
Satiation
Inhibitory Postsynaptic Potentials
Messenger RNA
Benzodiazepines
Sprague Dawley Rats
Proteins
Eating
Western Blotting
Fats

All Science Journal Classification (ASJC) codes

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Cite this

@article{31e9b4594e664159be31d5d5ca0e4131,
title = "Perinatal high-fat diet alters development of GABAA receptor subunits in dorsal motor nucleus of vagus",
abstract = "Perinatal high-fat diet (pHFD) exposure increases the inhibition of dorsal motor nucleus of the vagus (DMV) neurons, potentially contributing to the dysregula-tion of gastric functions. The aim of this study was to test the hypothesis that pHFD increases the inhibition of DMV neurons by disrupting GABAA receptor subunit development. In vivo gastric recordings were made from adult anesthetized Sprague-Dawley rats fed a control or pHFD (14 or 60{\%} kcal from fat, respectively) from embryonic day 13 (E13) to postnatal day 42 (P42), and response to brainstem microinjection of benzodiazepines was assessed. Whole cell patch clamp recordings from DMV neurons assessed the functional expression of GABAA α subunits, whereas mRNA and protein expression were measured via qPCR and Western blotting, respectively. pHFD decreased basal antrum and corpus motility, whereas brainstem microinjection of L838,417 (positive allosteric modulator of α2/3 subunit-containing GABAA receptors) produced a larger decrease in gastric tone and motility. GABAergic miniature inhibitory postsynaptic currents in pHFD DMV neurons were responsive to L838,417 throughout development, unlike control DMV neurons, which were responsive only at early postnatal timepoints. Brainstem mRNA and protein expression of the GABAA α1,2, and3 subunits, however, did not differ between control and pHFD rats. This study suggests that pHFD exposure arrests the development of synaptic GABAA α2/3 receptor subunits on DMV neurons and that functional synaptic expression is maintained into adulthood, although cellular localization may differ. The tonic activation of slower GABAA α2/3 subunit-containing receptors implies that such developmental changes may contribute to the observed decreased gastric motility. NEW & NOTEWORTHY Vagal neurocircuits involved in the control of gastric functions, satiation, and food intake are subject to significant developmental regulation postnatally, with immature GABAA receptors expressing slower α2/3-subunits, whereas mature GABAA receptor express faster α1-subunits. After perinatal high-fat diet exposure, this developmental regulation of dorsal motor nucleus of the vagus (DMV) neurons is disrupted, increasing their tonic GABAergic inhibition, decreasing efferent output, and potentially decreasing gastric motility.",
author = "Courtney Clyburn and Howe, {Caitlin A.} and Amy Arnold and Lang, {Charles H.} and Travagli, {Renato Alberto} and Kirsteen Browning",
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language = "English (US)",
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Perinatal high-fat diet alters development of GABAA receptor subunits in dorsal motor nucleus of vagus. / Clyburn, Courtney; Howe, Caitlin A.; Arnold, Amy; Lang, Charles H.; Travagli, Renato Alberto; Browning, Kirsteen.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 317, No. 1, 01.07.2019, p. G40-G50.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Perinatal high-fat diet alters development of GABAA receptor subunits in dorsal motor nucleus of vagus

AU - Clyburn, Courtney

AU - Howe, Caitlin A.

AU - Arnold, Amy

AU - Lang, Charles H.

AU - Travagli, Renato Alberto

AU - Browning, Kirsteen

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N2 - Perinatal high-fat diet (pHFD) exposure increases the inhibition of dorsal motor nucleus of the vagus (DMV) neurons, potentially contributing to the dysregula-tion of gastric functions. The aim of this study was to test the hypothesis that pHFD increases the inhibition of DMV neurons by disrupting GABAA receptor subunit development. In vivo gastric recordings were made from adult anesthetized Sprague-Dawley rats fed a control or pHFD (14 or 60% kcal from fat, respectively) from embryonic day 13 (E13) to postnatal day 42 (P42), and response to brainstem microinjection of benzodiazepines was assessed. Whole cell patch clamp recordings from DMV neurons assessed the functional expression of GABAA α subunits, whereas mRNA and protein expression were measured via qPCR and Western blotting, respectively. pHFD decreased basal antrum and corpus motility, whereas brainstem microinjection of L838,417 (positive allosteric modulator of α2/3 subunit-containing GABAA receptors) produced a larger decrease in gastric tone and motility. GABAergic miniature inhibitory postsynaptic currents in pHFD DMV neurons were responsive to L838,417 throughout development, unlike control DMV neurons, which were responsive only at early postnatal timepoints. Brainstem mRNA and protein expression of the GABAA α1,2, and3 subunits, however, did not differ between control and pHFD rats. This study suggests that pHFD exposure arrests the development of synaptic GABAA α2/3 receptor subunits on DMV neurons and that functional synaptic expression is maintained into adulthood, although cellular localization may differ. The tonic activation of slower GABAA α2/3 subunit-containing receptors implies that such developmental changes may contribute to the observed decreased gastric motility. NEW & NOTEWORTHY Vagal neurocircuits involved in the control of gastric functions, satiation, and food intake are subject to significant developmental regulation postnatally, with immature GABAA receptors expressing slower α2/3-subunits, whereas mature GABAA receptor express faster α1-subunits. After perinatal high-fat diet exposure, this developmental regulation of dorsal motor nucleus of the vagus (DMV) neurons is disrupted, increasing their tonic GABAergic inhibition, decreasing efferent output, and potentially decreasing gastric motility.

AB - Perinatal high-fat diet (pHFD) exposure increases the inhibition of dorsal motor nucleus of the vagus (DMV) neurons, potentially contributing to the dysregula-tion of gastric functions. The aim of this study was to test the hypothesis that pHFD increases the inhibition of DMV neurons by disrupting GABAA receptor subunit development. In vivo gastric recordings were made from adult anesthetized Sprague-Dawley rats fed a control or pHFD (14 or 60% kcal from fat, respectively) from embryonic day 13 (E13) to postnatal day 42 (P42), and response to brainstem microinjection of benzodiazepines was assessed. Whole cell patch clamp recordings from DMV neurons assessed the functional expression of GABAA α subunits, whereas mRNA and protein expression were measured via qPCR and Western blotting, respectively. pHFD decreased basal antrum and corpus motility, whereas brainstem microinjection of L838,417 (positive allosteric modulator of α2/3 subunit-containing GABAA receptors) produced a larger decrease in gastric tone and motility. GABAergic miniature inhibitory postsynaptic currents in pHFD DMV neurons were responsive to L838,417 throughout development, unlike control DMV neurons, which were responsive only at early postnatal timepoints. Brainstem mRNA and protein expression of the GABAA α1,2, and3 subunits, however, did not differ between control and pHFD rats. This study suggests that pHFD exposure arrests the development of synaptic GABAA α2/3 receptor subunits on DMV neurons and that functional synaptic expression is maintained into adulthood, although cellular localization may differ. The tonic activation of slower GABAA α2/3 subunit-containing receptors implies that such developmental changes may contribute to the observed decreased gastric motility. NEW & NOTEWORTHY Vagal neurocircuits involved in the control of gastric functions, satiation, and food intake are subject to significant developmental regulation postnatally, with immature GABAA receptors expressing slower α2/3-subunits, whereas mature GABAA receptor express faster α1-subunits. After perinatal high-fat diet exposure, this developmental regulation of dorsal motor nucleus of the vagus (DMV) neurons is disrupted, increasing their tonic GABAergic inhibition, decreasing efferent output, and potentially decreasing gastric motility.

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