Functional and molecular plasticity of {gamma} and {alpha}1 GABAA receptor subunits in the dorsal motor nucleus of the vagus after experimentally induced diabetes

Chronic experimentally induced hyperglycemia augments subunit-specific -aminobutyric acid A (GABA_A) receptor-mediated inhibition of parasympathetic preganglionic motor neurons in the dorsal motor nucleus of the vagus (DMV). However, the contribution of α1 or GABA_A receptor subunits, which are ubiquitously expressed on central nervous system neurons, to this elevation in inhibitory tone have not been determined. This study investigated the effect of chronic hyperglycemia/hypoinsulinemia on α1- and -subunit-specific GABA_A receptor-mediated inhibition using electrophysiological recordings in vitro and quantitative RT-PCR. DMV neurons from streptozotocin-treated mice demonstrated enhancement of both phasic and tonic inhibitory currents in response to application of the α1-subunit-selective GABA_A receptor-positive allosteric modulator zolpidem. Responses to low concentrations of the GABA_A receptor antagonist gabazine suggested an additional increased contribution of -subunit-containing receptors to tonic currents in DMV neurons. Consistent with the functional elevation in α1- and -subunit-dependent activity, transcription of both the α1- and 2-subunits was increased in the dorsal vagal complex of streptozotocin-treated mice. Overall, these findings suggest an increased sensitivity to both zolpidem and gabazine after several days of hyperglycemia/hypoinsulinemia, which could contribute to altered parasympathetic output from DMV neurons in diabetes.

NEW & NOTEWORTHY Glutamate and GABA signaling in the dorsal vagal complex is elevated after several days of chronic hyperglycemia in a mouse model of type 1 diabetes. We report persistently enhanced GABA_A receptor-mediated responses to the somnolescent zolpidem in preganglionic vagal motor neurons. These results imply a broader impact of chronic hyperglycemia on central vagal function than previously appreciated and reinforce the hypothesis that diabetes effects in the brain can impact regulation of metabolic homeostasis.

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