d-Glucose modulates synaptic transmission from the central terminals of vagal afferent fibers

Abstract

Wan S, Browning KN. D-Glucose modulates synaptic transmission from the central terminals of vagal afferent fibers. Am J Physiol Gastrointest Liver Physiol 294: G757-G763, 2008. First published January 17, 2008 doi:10.1152/ajpgi.00576.2007.-Experimental evidence suggests that glucose modulates gastric functions via vagally mediated effects. It is unclear whether glucose affects only peripheral vagal nerve activity or whether glucose also modulates vagal circuitry at the level of the brain stem. This study used whole cell patch-clamp recordings from neurons of the nucleus of the tractus solitarius (NTS) to assess whether acute variations in glucose modulates vagal brain stem neurocircuitry. Increasing D-glucose concentration induced a postsynaptic response in 40% of neurons; neither the response type (inward vs. outward current) nor response magnitude was altered in the presence of tetrodotoxin suggesting direct effects on the NTS neuronal membrane. In contrast, reducing D-glucose concentration induced a postsynaptic response (inward or outward current) in 54% of NTS neurons; tetrodotoxin abolished these responses, suggesting indirect sites of action. The frequency, but not amplitude, of spontaneous and miniature excitatory postsynaptic currents (EPSCs) was correlated with D-glucose concentration in 79% of neurons tested (n ϭ 48). Prior surgical afferent rhizotomy abolished the ability of D-glucose to modulate spontaneous EPSC frequency, suggesting presynaptic actions at vagal afferent nerve terminals to modulate glutamatergic synaptic transmission. In experiments in which EPSCs were evoked via electrical stimulation of the tractus solitarius, EPSC amplitude correlated with D-glucose concentration. These effects were not mimicked by L-glucose, suggesting the involvement of glucose metabolism, not uptake, in the nerve terminal. These data suggest that the synaptic connections between vagal afferent nerve terminals and NTS neurons are a strong candidate for consideration as one of the sites where glucose-evoked changes in vagovagal reflexes occurs. brain stem; electrophysiology; vagus DELAYED GASTRIC EMPTYING, or gastroparesis (diabetic gastropathy) in its extreme state, is reported in ϳ35-50% of patients with Type 1 or Type 2 diabetes (17,25,44,52) and is associated with early satiety, nausea, vomiting, and abdominal pain. Autonomic nerve dysfunction(s) undoubtedly contribute to the development of this syndrome (52), but reports that physiological hyperglycemia delays gastric emptying have led to the understanding that poor glycemic control per se may be responsible for at least some of these symptoms (25,26,37,38,45). Acute changes in blood glucose concentration, even within the physiological range, have profound effects on gastrointestinal functions, including gastric emptying. In healthy subjects, gastric emptying of both solids and liquids is slower at a blood glucose concentration of 8 mM than at 4 mM, and profound hyperglycemia (15 mM) causes a clear relaxation of the proximal stomach (29, 37). Hypoglycemia,...

Molecular and functional changes in glucokinase expression in the brainstem dorsal vagal complex in a murine model of type 1 diabetes

“…In the presence of TTX (2 µM) to prevent action potential firing, there was no significant effect of GA on miniature EPSC (mEPSC) frequency in control mice (p>0.05); mEPSC frequency was decreased slightly in only one of five neurons from three mice, so effects in STZ-treated mice were not assessed. These findings are consistent with an effect of GCK in mediating spontaneous excitatory synaptic responses to ambient glucose levels in NTS neurons (Wan and Browning, 2008) and indicated that GCK blockade inhibited excitatory, glutamatergic synaptic input to most GABA neurons.…”

“…Despite this hypothalamic focus, abundant evidence indicates that brainstem dorsal vagal complex (DVC) plays a primary and critical role in glucose-sensitive modulation of plasma glucose and insulin levels, feeding and energy balance Zsombok and Smith 2009). Subsets of DVC neurons and synaptic terminals are glucose-sensitive (Balfour et al 2006;Boychuk et al 2015a;Browning 2013;Lamy et al 2014;Wan et al 2008), consistent with longstanding evidence that glucose-sensing neurons in this region regulates both feeding and blood glucose concentrations . Injection of a glucoprivic glucose analogue into the vagal complex, but not hypothalamic areas, increases both feeding and hyperglycemia in rats .…”

“…Since hypoglycemia is a hallmark of the model used in these studies, it is possible that reduced insulin levels may also contribute to the changes observed here. Alternatively, glutamate is the primary neurotransmitter released by viscerosensory afferents, and elevated glucose concentration enhances glutamate release from these terminals (Boychuk et al 2015a;Wan and Browning 2008). In addition, glutamate release is chronically increased in the DMV of diabetic mice (Bach et al 2015;Zsombok et al 2011).…”

“…Neurons in the NTS normally respond to elevated or reduced glucose concentration with either increases or decreases in excitability (Balfour et al 2006;Boychuk et al 2015a;Browning 2013;Lamy et al 2014;Wan et al 2008), which are often GCK-dependent.…”

“…Vagal afferents rapidly convey information about gastrointestinal distention and nutrient content to the NTS, where that information is processed, integrated with neuronal and humoral signals, and transmitted to other brain areas, including to vagal motor neurons of the dorsal motor nucleus of the vagus (DMV). Neurons in the NTS respond to acutely altered glucose concentration with either increases or decreases in 3 neural excitability and altered synaptic input , Balfour et al, 2006, Wan and Browning, 2008, Lamy et al, 2014, Boychuk et al, 2015a, which are glucokinase (GCK)-dependent. The depolarizing response is mediated by inactivation of ATP-sensitive K + (KATP) channels (Balfour et al, 2006, Boychuk et al, 2015a and KATP channel modulation prevents the glucose-induced, GABA mediated inhibition of vagal motor neurons .…”