Glutamatergic drive facilitates synaptic inhibition of dorsal vagal motor neurons after experimentally induced diabetes in mice

Abstract

The role of central regulatory circuits in modulating diabetes-associated glucose dysregulation has only recently been under rigorous investigation. One brain region of interest is the dorsal motor nucleus of the vagus (DMV), which contains preganglionic parasympathetic motor neurons that regulate subdiaphragmatic visceral function. Previous research has demonstrated that glutamatergic and GABAergic neurotransmission are independently remodeled after chronic hyperglycemia/hypoinsulinemia. However, glutamatergic circuitry within the dorsal brain stem impinges on GABAergic regulation of the DMV. The present study investigated the role of glutamatergic neurotransmission in synaptic GABAergic control of DMV neurons after streptozotocin (STZ)-induced hyperglycemia/hypoinsulinemia by using electrophysiological recordings in vitro. The frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) was elevated in DMV neurons from STZ-treated mice. The effect was abolished in the presence of the ionotropic glutamate receptor blocker kynurenic acid or the sodium channel blocker tetrodotoxin, suggesting that after STZ-induced hyperglycemia/hypoinsulinemia, increased glutamatergic receptor activity occurs at a soma-dendritic location on local GABA neurons projecting to the DMV. Although sIPSCs in DMV neurons normally demonstrated considerable amplitude variability, this variability was significantly increased after STZ-induced hyperglycemia/hypoinsulinemia. The elevated amplitude variability was not related to changes in quantal release, but rather correlated with significantly elevated frequency of sIPSCs in these mice. Taken together, these findings suggest that GABAergic regulation of central vagal circuitry responsible for the regulation of energy homeostasis undergoes complex functional reorganization after several days of hyperglycemia/hypoinsulinemia, including both glutamate-dependent and -independent forms of plasticity.

Functional and molecular plasticity of γ and α1 GABAA receptor subunits in the dorsal motor nucleus of the vagus after experimentally induced diabetes

“…Although STZ-induced hyperglycemia/hypoinsulinemia results in elevated glutamatergic facilitation of GABA release (Boychuk and Smith 2016), the present study confirms previous reports that GABAergic sIPSC frequency was similar when ionotropic glutamate receptors are blocked (Boychuk et al 2015b). It also extends this work by demonstrating that sIPSC frequency, amplitude, and decay time constant remained similar between the two groups after GABA concentration was experimentally elevated in the perfusate, and the values for all sIPSC measures reported in the presence of elevated GABA concentration are comparable to those reported in the presence of normal ambient GABA concentration (Boychuk et al 2015b;Boychuk and Smith 2016). However, hyperglycemia/ hypoinsulinemia resulted in a ZOL-induced augmentation of mean sIPSC decay time in DMV neurons from diabetic mice, suggesting an overall increased effect of ZOL on phasic current.…”

“…Therefore, the increase in the functional expression of GBZ-sensitive tonic current likely reflects the increased transcriptional expression of the ␥2-subunit. Factors that might induce the increased transcription of GABA receptor subunits include plasticity events that occur subsequent to decreased insulin levels or to the chronically increased glucose, GABA (Boychuk et al 2015b), or glutamate (Boychuk and Smith 2016;Zsombok et al 2011) concentrations in the DMV of STZ-treated mice. Although direct effects of STZ in the DMV are unlikely several days postinjection, because the drug is rapidly cleared from serum (Karunanayake et al 1974;Schein and Loftus 1968) and the STZ treatment does not induce cell death in the vagal complex (Bach et al 2015), other effects secondary to STZ treatment (e.g., sustained inflammatory responses; STZ-or hyperglycemia-induced damage to vagal afferents or enteric neurons) might also contribute to the changes observed.…”

“…In contrast, acutely elevated glucose concentration consistently hyperpolarizes the membrane of DMV neurons in a manner consistent with increased GABA release and subsequent activation of tonic GABA currents in the DMV (Ferreira et al 2001), and GABAergic NTS neurons are glucose sensitive (Boychuk et al 2015a). In addition, glutamatergic modulation of GABAergic phasic currents in DMV neurons is elevated after hyperglycemia/hypoinsulinemia is experimentally induced (Boychuk and Smith 2016), which could contribute to chronically elevated GABA concentrations in vivo. Moreover, DMV neurons from hyperglycemic mice demonstrate a sustained elevation of tonic current signaling mediated by GABA A receptors containing ␦-subunits, and this elevation involves posttranslational modification of receptor function (Boychuk et al 2015b).…”

“…Whereas increased functional expression of ␦-subunit-containing receptors has been reported after several days of systemic hyperglycemia (Boychuk et al 2015b), diabetes-associated plasticity of GABA A receptors containing ␣1/␥2-subunits has not been investigated adequately in the DMV. Given that GABA concentration in the dorsal vagal complex is likely to be elevated after chronic hyperglycemia (Boychuk and Smith 2016), this is a significant oversight. Therefore, the present study tested whether GABAergic signaling arising from postsynaptic receptors containing either the ␣1or ␥-subunit was significantly altered in DMV neurons after chronic hyperglycemia/hypoinsulinemia in a mouse model of type 1 diabetes.…”

Gut–Brain Axis in Regulation of Blood Pressure

“…GABAergic neurons are present and involved in regulation of excitation of several cardioregulatory brain regions, and modulation of vagal signaling within the NTS. Elevated GABA signaling in the NTS has been associated with HTN (Li et al, 2013 ) and diabetes (Boychuk and Smith, 2016 ). GABA is also an essential cardioregulatory neurotransmitter in the paraventricular nucleus (PVN) of hypothalamus, where it reportedly contributes to determining the level of sympathetic outflow.…”