GABAergic modulation of ventilation in mdx mice: A murine model of muscular dystrophy
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Duchene Muscular Dystrophy (DMD) results from the lack of dystrophin-A structural protein playing an important role in the clustering of GABA receptors at post-synaptic neural membranes. Although the absence of dystrophin has been linked to altered GABA function in various cortical regions associated with neurocognitive pathways, to date no study has investigated whether GABAergic mechanisms in ventilatory control pathways are altered in DMD. We investigated whether GABA A or GABA B receptor function is preserved in the mdx mouse, a murine model of DMD. Studies were performed on 8 mdx (C57BL/10ScSn-DMDmdx/J) and 9 non-mdx control (C57BL/10ScSnJ) 5-month old mice. Breathing frequency (f), tidal volume (VT) and minute ventilation (VE) were measured in conscious mice with barometric plethysmography during room air breathing, after 5 min of hypoxia (10% O 2 ), and after 5 min of hypercapnea (4% CO 2 ). Studies were conducted on three separate occasions (72 hours between tests) following the random subcutaneous injection of equal volumes with either Bicuculline (selective GABA A antagonist, 0.5mg/kg), Phaclofen (selective GABA B antagonist, 1mg/kg) or DMSO (vehicle). The response of mdx mice following drug injection was considered abnormal if it was different from the average response from normal mice. Blockade of GABA A receptors with Bicuculline produced similar effects on ventilation in normal and mdx mice during room air, hypoxia, and during hypercapnia. In contrast, blockade of GABA B receptors with Phaclofen resulted in different responses in control and mdx mice during room air and hypoxia, but not during hypercapnia. We conclude that endogenous GABA acting on GABA A receptors are well preserved in the modulation of breathing in mdx mice, whereas GABA acting on GABA B receptor pathways is abnormal in mdx mice. Our findings should encourage further research on targeting neural control of ventilation in DMD.