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 gamma-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 (q)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.

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