Key result
Type-1 diabetes in mice increases GABAA receptor sensitivity, driving larger outward currents in DMV neurons.
Why the study?
Autonomic dysregulation in type-1 diabetes involves altered synaptic regulation of parasympathetic preganglionic motor neurons in the dorsal motor nucleus of the vagus, but the effects on GABAA receptor-mediated inhibition are not fully understood.
Chronic hyperglycemia/hypoinsulinemia in type-1 diabetes increases the sensitivity of δ-subunit containing GABAA receptors in DMV neurons, which may contribute to diabetic autonomic dysregulation.
Does not inform clinical diabetes management; leaves open δ-GABAA contributions to human vagal dysfunction.
Autonomic dysregulation accompanies type-1 diabetes, and synaptic regulation of parasympathetic preganglionic motor neurons in the dorsal motor nucleus of the vagus (DMV) is altered after chronic hyperglycemia/hypoinsulinemia. Tonic gamma-aminobutyric acid A (GABAA) inhibition prominently regulates DMV neuron activity, which contributes to autonomic control of energy homeostasis. This study investigated persistent effects of chronic hyperglycemia/hypoinsulinemia on GABAA receptor-mediated inhibition in the DMV after streptozotocin-induced type-1 diabetes using electrophysiological recordings in vitro, quantitative (q)RT-PCR, and immunohistochemistry. Application of the nonspecific GABAA receptor agonist muscimol evoked an outward current of significantly larger amplitude in DMV neurons from diabetic mice than controls. Results from application of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol hydrochloride (THIP), a δ-subunit agonist, suggested that GABAA receptors containing δ-subunits contributed to the enhanced inducible tonic GABA current in diabetic mice. Sensitivity to THIP of inhibitory postsynaptic currents in DMV neurons from diabetic mice was also increased. Results from qRT-PCR and immunohistochemical analyses indicated that the altered GABAergic inhibition may be related to increased trafficking of GABAA receptors that contain the δ-subunit, rather than an expression change. Overall these findings suggest increased sensitivity of δ-subunit containing GABAA receptors after several days of hyperglycemia/hypoinsulinemia, which dramatically alters GABAergic inhibition of DMV neurons and could contribute to diabetic autonomic dysregulation.
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Boychuk et al. (2015) studied Type-1 diabetes. Streptozotocin-induced type-1 diabetes vs. Controls was evaluated on GABAA receptor-mediated inhibition in the dorsal motor nucleus of the vagus. Streptozotocin-induced type-1 diabetes in mice increased the sensitivity of δ-subunit containing GABAA receptors, resulting in significantly larger amplitude outward currents in DMV neurons.
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