Changes in ventral respiratory column GABAaR ε- and δ-subunits during hibernation mediate resistance to depression by EtOH and pentobarbital

Am J Physiol Regul Integr Comp Physiol. 2011 Feb;300(2):R272-83. doi: 10.1152/ajpregu.00607.2010. Epub 2010 Nov 17.


During hibernation in the 13-lined ground squirrel, Ictidomys tridecemlineatus, the cerebral cortex is electrically silent, yet the brainstem continues to regulate cardiorespiratory function. Previous work showed that neurons in slices through the medullary ventral respiratory column (VRC) but not the cortex are insensitive to high doses of pentobarbital during hibernation, leading to the hypothesis that GABA(A) receptors (GABA(A)R) in the VRC undergo a seasonal modification in subunit composition. To test whether alteration of GABA(A)R subunits are responsible for hibernation-associated pentobarbital insensitivity, we examined an array of subunits using RT-PCR and Western blots and identified changes in ε- and δ-subunits in the medulla but not the cortex. Using immunohistochemistry, we confirmed that during hibernation, the expression of ε-subunit-containing GABA(A)Rs nearly doubles in the VRC. We also identified a population of δ-subunit-containing GABA(A)Rs adjacent to the VRC that were differentially expressed during hibernation. As δ-subunit-containing GABA(A)Rs are particularly sensitive to ethanol (EtOH), multichannel electrodes were inserted in slices of medulla and cortex from hibernating squirrels and EtOH was applied. EtOH, which normally inhibits neuronal activity, excited VRC but not cortical neurons during hibernation. This excitation was prevented by bicuculline pretreatment, indicating the involvement of GABA(A)Rs. We propose that neuronal activity in the VRC during hibernation is unaffected by pentobarbital due to upregulation of ε-subunit-containing GABA(A)Rs on VRC neurons. Synaptic input from adjacent inhibitory interneurons that express δ-subunit-containing GABA(A)Rs is responsible for the excitatory effects of EtOH on VRC neurons during hibernation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Animals
  • Bicuculline / pharmacology
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / physiology
  • Ethanol / pharmacology*
  • GABA-A Receptor Antagonists / pharmacology
  • Gene Expression / genetics
  • Gene Expression Regulation / physiology*
  • Hibernation / physiology*
  • Medulla Oblongata / drug effects
  • Medulla Oblongata / physiology*
  • Neurons / drug effects
  • Neurons / physiology
  • Pentobarbital / pharmacology*
  • Protein Subunits / genetics
  • Protein Subunits / metabolism*
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism*
  • Sciuridae
  • Solitary Nucleus / drug effects
  • Solitary Nucleus / physiology
  • Synapses / metabolism
  • Synaptophysin / genetics


  • GABA-A Receptor Antagonists
  • Protein Subunits
  • Receptors, GABA-A
  • Synaptophysin
  • Ethanol
  • Pentobarbital
  • Bicuculline