Maternal High Fat Diet Increases an Inhibitory Extrasynaptic Tonic GABAA Current in Dorsal Motor Nucleus of the Vagus Neurons Regulating Gastric Functions

Abstract

The perinatal period is critically important in the development of autonomic neurocircuits innervating the gastrointestinal (GI) tract influencing gastric emptying and appetite regulation. Developmental alterations may affect these GI neurocircuits possibly contributing to the energy imbalance seen in obesity. Previous studies suggest there is an increased GABAergic inhibition of gastric projecting dorsal motor nucleus of the vagus nerve (DMV) neurons in the brainstem of rats fed a high fat diet (HFD) during the perinatal period, but the underlying neural mechanisms and the effects on gastric motility have yet to be clarified. The aims of this study was to assess the effects of perinatal HFD on (i) inhibitory synaptic inputs to gastric‐projecting DMV neurons and (ii) gastric tone and motility.Whole cell patch clamp recordings were made from gastric projecting DMV neurons in thin brainstem slices from Sprague‐Dawley rats (4–6 weeks of age) fed either a control or HFD (14 or 60%kcal from fat, respectively) from embryonic day 13.In the present study, perinatal HFD rats were not significantly heavier than age‐matched control rats (6 weeks; 232±17g vs 209±5g). Superfusion with the non‐selective GABAA receptor antagonist, bicuculline (50μM), induced a larger inward current in DMV neurons from perinatal HFD vs control animals (55.7±14.1pA vs 21.7±1.7pA, n=8, P<0.05), suggesting a greater overall tonic inhibition. While superfusion with the phasic (synaptic) GABAA receptor antagonist, gabazine (25μM), did not reveal any difference in the resulting inward current between perinatal HFD vs control DMV neurons (11.2±1.4pA vs 6.7±1.5pA, n=6, P>0.05), the addition of bicuculline into the bath uncovered a larger tonic (extrasynaptic) GABAA current in perinatal HFD vs control DMV neurons (36.4±3.47pA vs 20.8±2.24pA, n=6, P<0.05), suggesting that the greater overall inhibition of perinatal DMV neurons results from a larger tonic GABAA current.The studies imply that perinatal overnutrition increases the tonic GABAergic inhibition of gastric projecting DMV neurons via an increase in activation of extrasynaptic GABAA receptors. Such alterations in brainstem neurocircuit development as a consequence of maternal over‐nutrition may induce gastric dysmotility and dysregulated gastointestinal reflexes, hence influence offspring to develop obesity.Support or Funding InformationFunded by NIH 078364 and NSF IOS1148978