Acute High‐Fat Diet Induced Modulation of Glutamatergic Currents in Dorsal Motor Nucleus of the Vagus Neurons is Dependent on Activation of Extrasynaptic NMDA Receptors

Following HFD exposure, both humans and experimental animals undergo a brief period of hyperphagia (1–2 days), before caloric balance is restored (3–5 days). We showed previously that acute HFD increases glutamatergic transmission to neurons of the dorsal motor nucleus of the vagus (DMV) via activation of synaptic NMDA receptors (NMDA‐R), increasing motoneuron excitability and efferent control of gastric function (PMID: 29368945) although the mechanism responsible has not been elucidated. Previous studies have suggested, however, that activation of extrasynaptic NMDA‐Rs may cause sufficient local depolarization to remove the Mg 2+ block on NMDA‐Rs, allowing for their activation. The purpose of this study is to test the hypothesis that the increased synaptic NMDA‐R activation in DMV neurons following acute HFD exposure occurs subsequent to activation of extrasynaptic NMDA‐R. Whole‐cell patch clamp recordings were made from gastric‐projecting DMV neurons in thin (300μm) brainstem slices of Sprague‐Dawley rats, 4–6 weeks of age. Rats were fed control or HFD (14% and 60% kcal from fat, respectively) for 3–5 days prior to experimentation. The effects of increasing (from 1.2mM to 2.4mM) or decreasing (to 0.6mM) extracellular levels of Mg 2+ , the NMDA‐R antagonist memantine (30μM), and the glutamate uptake inhibitor, dihydrokainate (DHK; 30μM), on NMDA‐mediated miniature excitatory postsynaptic currents (mEPSCs) and DMV neuronal excitability (action potential firing rate; AP) were assessed. In vivo recordings of gastric tone and motility were made in response to brainstem microinjection of DHK or 4 th ventricular application of memantine (60pmol/60nL and 50pmol/2mL, respectively). Following acute HFD, the NMDA‐R antagonist AP5 (25mM) decreases mEPSC frequency and AP firing rate in DMV neurons; these actions were blocked by memantine (65.1±9% vs. 12.6±9% and 78.9±14% vs. 18.1±8%, respectively n=5–13, P<0.05). In control rate, however, increasing extracellular glutamate concentration with DHK uncovered inhibitory actions of AP5 on mEPSCs and AP firing rate (115.7±12% vs. 77.2%±6% and 87.6%±14% vs. 70.5%±16% respectively, n=5–15, P<0.05). Furthermore, increasing extracellular [Mg 2+ ] blocked the effects of AP5 following acute HFD exposure (89.0±25%, n=4, p>0.05) whereas decreasing the extracellular [Mg 2+ ] uncovered synaptic NMDA‐R mediated synaptic currents in control rats (48.6±5%, n=4, P<0.05). Preliminary in vivo recordings suggest that brainstem microinjection of memantine attenuated the glutamate‐dependent decrease in gastric tone and motility following acute HFD exposure, whereas DHK uncovered this effect in control rats. These data suggest that the acute HFD‐induced increase in synaptic NMDA‐R activation occurs following extrasynaptic NMDA‐R activation, although the source of this extrasynaptic glutamate remains to be elucidated. Understanding these mechanisms and, importantly, how they are lost following continued HFD exposure, may provide a mechanistic understanding of hyperphagia and weight gain as well as identify potential therapeutic targets for the treatment of obesity. Support or Funding Information NIH DK111667 to KNB This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .