Glucose increases synaptic transmission from vagal afferent central nerve terminals via modulation of 5-HT₃ receptors

Abstract

Acute hyperglycemia has profound effects on vagally mediated gastrointestinal functions. We have reported recently that the release of glutamate from the central terminals of vagal afferent neurons is correlated directly with the extracellular glucose concentration. The present study was designed to test the hypothesis that 5-HT(3) receptors present on vagal afferent nerve terminals are involved in this glucose-dependent modulation of glutamatergic synaptic transmission. Whole-cell patch-clamp recordings were made from neurons of the nucleus tractus solitarius (NTS) in thin rat brainstem slices. Spontaneous and evoked glutamate release was decreased in a concentration-dependent manner by the 5-HT(3) receptor selective antagonist, ondansetron. Alterations in the extracellular glucose concentration induced parallel shifts in the ondansetron-mediated inhibition of glutamate release. The changes in excitatory synaptic transmission induced by extracellular glucose concentration were mimicked by the serotonin uptake inhibitor, fenfluramine. These data suggest that glucose alters excitatory synaptic transmission within the rat brainstem via actions on tonically active 5-HT(3) receptors, and the number of 5-HT(3) receptors on vagal afferent nerve terminals is positively correlated with the extracellular glucose concentration. These data indicate that the 5-HT(3) receptors present on synaptic connections between vagal afferent nerve terminals and NTS neurons are a strong candidate for consideration as one of the sites where glucose acts to modulate vagovagal reflexes.

Glycemic state regulates melanocortin, but not nesfatin-1, responsiveness of glucose-sensing neurons in the nucleus of the solitary tract

“…Our chosen concentrations of 0.2, 3, and 5 mM extracellular glucose, therefore, provide a closer mimic of the range of concentrations that may be encountered by NTS neurons in vivo than previous whole cell patch-clamp studies in the region, where large decreases from 10 to 3 or 0 mM, or large increases from elevated baselines of 10 mM to 20 or 30 mM glucose have been used (2,40). These studies, as well as others using extracellular recordings, have found between 20 and 81% of NTS neurons respond to changes in extracellular glucose concentrations, with contradicting reports of the predominance of GE vs. GI phenotypes (2,10,28,40,41,47). Our observation that 56% of NTS neurons are glucose-responsive is similar to those of the most physiological previous studies, where 51-56% of NTS neurons responded to 2 mM changes in glucose concentrations.…”

Central Nervous System Control of Gastrointestinal Motility and Secretion and Modulation of Gastrointestinal Functions

“…As with vagal sensory somata, glucose induces the trafficking of 5-HT3 receptors to the membrane of vagal sensory terminals, the tonic activation of which increases glutamate release onto NTS neurons (528). Earlier studies have also shown that glucose is able to modulate the activity of brainstem neurons; hepatic vagal afferent fibers that were inhibited by an increase in glucose levels, for example, innervate NTS neurons that are also inhibited by local application of glucose (3), whereas other NTS neurons are excited by an increase in glucose levels (2, 124, 125, 543, 544).…”

Modulation of gastrointestinal vagal neurocircuits by hyperglycemia

“…Further studies demonstrated that, as with vagal sensory somata, glucose induces the trafficking of 5-HT3 receptors to the membrane of vagal sensory nerve terminals, the activation of which increases glutamate release (Wan and Browning, 2008b). 5-HT 3 receptors on vagal afferent terminals appear to be activated tonically; in fact, the 5-HT 3 receptor antagonist, ondansetron, decreases action potential dependent and independent synaptic transmission to second order NTS neurons implying an ongoing activation of these receptors (Wan and Browning, 2008b).…”