Seasonally altered GABAA receptors in medullary cardiorespiratory nuclei make neurons unresponsive to high doses of pentobarbital in hibernating, but not summer active, ground squirrels

The 13‐lined ground squirrel ( Spermophilus tridecemlineatus ), a hibernating species, is a natural model of extreme physiology. In torpor, body temperature drops to 0‐4 °C and the cortex is electrically silent, but the brainstem continues to regulate cardiorespiratory function. We hypothesize that this differential regulation of neuronal function is due to altered GABA A receptor function. To test this hypothesis, neuronal firing rates were recorded from medullary and cortical slices from aroused hibernators and summer active squirrels using multichannel recording techniques. During the hibernation season, medullary neuron firing rates were unchanged by pentobarbital (300 μM), whereas cortical neurons stopped firing action potentials. We confirmed that pentobarbital acts on cortical GABA A receptors. Further, we show that functional GABA A receptors are present in the medulla (NTS and VRG) during hibernation and that receptors' sensitivity to GABA does not change. Western blot analyses show that GABA A receptors undergo a seasonal modification in subunit composition. During hibernation, α 5 subunit expression is increased in cortex and δ is increased in medulla, with posttranslational modification of the δsubunit. These data provide insights into natural mechanisms whereby brainstem function can be sustained in extreme conditions and clinically relevant pharmacological challenges.