title: Diabetes induces GABA receptor plasticity in murine vagal motor neurons.
abstract: 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.
authors.affiliation: Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky.
authors.forename: C R
authors.initials: CR
authors.lastname: Boychuk
authors.affiliation: Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky.
authors.forename: K Cs
authors.initials: KC
authors.lastname: Halmos
authors.affiliation: Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky bret.smith@uky.edu.
authors.forename: B N
authors.initials: BN
authors.lastname: Smith
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D018755:GABA Agonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D007150:Immunohistochemistry; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D009118:Muscimol / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D060888:Real-Time Polymerase Chain Reaction; D011963:Receptors, GABA-A / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D014630:Vagus Nerve / Q000187:drug effects / Q000503:physiopathology*
chemical_list: D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D007555:Isoxazoles; D011963:Receptors, GABA-A; D009118:Muscimol; C015542:gaboxadol
keywords: GABA; diabetes; tonic current