DMV extrasynaptic NMDA receptors regulate caloric intake in rats
Courtney Clyburn, R. Alberto Travagli, Amy C. Arnold, Kirsteen N. Browning
Courtney Clyburn, R. Alberto Travagli, Amy C. Arnold, Kirsteen N. Browning
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Research Article Gastroenterology Neuroscience

DMV extrasynaptic NMDA receptors regulate caloric intake in rats

Abstract

Acute high-fat diet (aHFD) exposure induces a brief period of hyperphagia before caloric balance is restored. Previous studies have demonstrated that this period of regulation is associated with activation of synaptic N-methyl-D-aspartate (NMDA) receptors on dorsal motor nucleus of the vagus (DMV) neurons, which increases vagal control of gastric functions. Our aim was to test the hypothesis that activation of DMV synaptic NMDA receptors occurs subsequent to activation of extrasynaptic NMDA receptors. Sprague-Dawley rats were fed a control or high-fat diet for 3–5 days prior to experimentation. Whole-cell patch-clamp recordings from gastric-projecting DMV neurons; in vivo recordings of gastric motility, tone, compliance, and emptying; and food intake studies were used to assess the effects of NMDA receptor antagonism on caloric regulation. After aHFD exposure, inhibition of extrasynaptic NMDA receptors prevented the synaptic NMDA receptor–mediated increase in glutamatergic transmission to DMV neurons, as well as the increase in gastric tone and motility, while chronic extrasynaptic NMDA receptor inhibition attenuated the regulation of caloric intake. After aHFD exposure, the regulation of food intake involved synaptic NMDA receptor–mediated currents, which occurred in response to extrasynaptic NMDA receptor activation. Understanding these events may provide a mechanistic basis for hyperphagia and may identify novel therapeutic targets for the treatment of obesity.

Authors

Courtney Clyburn, R. Alberto Travagli, Amy C. Arnold, Kirsteen N. Browning

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Figure 3

Extrasynaptic NMDAR activation is required for the synaptic NMDAR–mediated decrease in action potential firing rate.

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Extrasynaptic NMDAR activation is required for the synaptic NMDAR–mediat...
(A and B) Representative traces from gastric-projecting control (A) and aHFD (B) DMV neurons current-clamped at a potential to allow action potential firing at approximately 1 Hz. In controls (A), perfusion with memantine (30 μM; left, middle) or AP5 (25 μM; left, bottom) had no effect on action potential firing rate. Perfusion with DHK, however, increased action potential firing rate (30 μM; right, middle) and uncovered an AP5-mediated decrease in action potential firing rate (right, bottom). In aHFD neurons (B), perfusion with memantine (30 μM; left, middle) had no effect on action potential firing rate but blocked the subsequent AP5-mediated decrease (25 μM; left, bottom) and perfusion with DHK (30 μM; right, middle) had no effect on action potential firing rate and did not affect the observed AP5-mediated decrease (right, bottom). (C and D) Graphical summary of the effects of memantine (C; left, n = 11 cells, 5 rats) (D; left, n = 9 cells, 4 rats), DHK (C; right; n = 16 cells, 6 rats) (D; middle; n = 9 cells, 3 rats), and AP5 on action potential firing rate in control (C) and aHFD (D) DMV neurons. In controls (C), application of memantine and AP5 had no effect on action potential firing rate. Application of DHK, however, significantly increased action potential firing rate in control conditions, which uncovered an AP5-mediated decrease in action potential firing rate. After aHFD exposure (D), application of memantine (left) and ConG (right; n = 6 cells, 3 rats) attenuated the AP5-mediated decrease in action potential firing rate observed after aHFD exposure. Application of DHK had no significant effect on action potential firing rate and did not affect the AP5-mediated decrease observed normally. *P < 0.05 versus DHK #P < 0.05 versus baseline (Student’s paired t test).