High‐Fat Diet Induced Modulation of Glutamatergic Currents in the Neurons of the Dorsal Motor Nucleus of the Vagus is Dependent on Activation of Extrasynaptic NMDA Receptors
Authors: Clyburn Courtney , Travagli Alberto , Browning Kirsteen N. 
Published: June 2021

Diet‐induced obesity (DIO) and exposure to a high‐fat diet (HFD) has been shown to modulate neurotransmission in many areas of the brainstem, including vagal neurocircuits, which can have profound effects on gastric functions and feeding behavior. We have demonstrated previously that acute exposure to HFD modulates glutamatergic transmission in the dorsal motor nucleus of the vagus (DMV), increasing synaptic NMDA currents, DMV neuronal excitability and, in turn, gastric tone and motility. The mechanism that results in this increased NMDA current following acute exposure to HFD has, however, not been examined. Previous studies have suggested that activation of extrasynaptic NMDA receptors may cause sufficient local depolarization to remove the Mg2+ block on synaptic NMDA receptors, allowing for their activation. The purpose of this study is to test the hypothesis that, extrasynaptic NMDA receptor activation facilitates acute HFD‐mediated alterations in synaptic NMDA receptor activation.Whole cell patch clamp recordings of gastric‐projecting DMV neurons were made from thin (300μm) brainstem slices of Sprague‐Dawley rats, 4–6 weeks of age. Rats were fed a control diet (14% kcal from fat) throughout the study, or a HFD (60% kcal from fat) for 3–5 days prior to experimentation. The effects of increasing extracellular levels of Mg2+ in the perfusate (from 1.2mM to 2.4 or 4.8mM) and the extrasynaptic NMDA receptor antagonist memantine (30mM), on synaptic NMDA‐receptor mediated miniature excitatory postsynaptic currents (mEPSCs) and DMV neuronal excitability were assessed.Following acute HFD exposure, the NMDA receptor antagonist AP5 (25mM), decreased mEPSC frequency in 6/15 neurons (1.36±.3 vs .5±.1 pulses per second (p.p.s.), P<0.05). In the presence of memantine, however, which itself decreased mEPSC frequency (3.7±1.7 vs 5.0±1.7 p.p.s., N=4, P<0.05), AP5 had no effect on mEPSC frequency or amplitude (97±5% and 101±0.8% change from baseline of memantine alone, respectively, P>0.05). Furthermore, preliminary evidence suggests that memantine decreases the ability of AP5 to inhibit action potential firing rate and, further, that increasing the [Mg2+] in the perfusate significantly reduces mEPSC frequency (62% of control in the presence of 2.4mM, and 50% of control in the presence of 4.8mM Mg2+).These data suggest that the increased activation of synaptic NMDA receptors observed in response to acute HFD occurs subsequent to activation of extrasynaptic NMDA receptors which may, in turn, be caused by glutamate spillover from the synaptic cleft or release of glutamate from nearby astrocytes. Increasing glutamatergic signaling via modulation of extrasynaptic and synaptic NMDA receptor activation may be an important means by which DMV neuronal excitability is increased following acute HFD exposure. The consequent increase in gastric motility and tone may be an important physiological homeostatic adaptive response involved in the regulation of caloric intake following exposure to a HFD.Support or Funding InformationNSF IOS1148978 to Kirsteen BrowningThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.