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ENVIRONMENTAL, EXERCISE AND RESPIRATORY PHYSIOLOGY

Adaptation to hypobaric hypoxia involves GABA_A receptors in the pons

¹Department of Pharmacology, ²Division of Pulmonary and Critical Care Medicine, Department of Medicine, and ³Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio

Submitted 14 May 2007 ; accepted in final form 30 November 2007

ABSTRACT

Survival in low-oxygen environments requires adaptation of sympathorespiratory control networks located in the brain stem. The molecular mechanisms underlying adaptation are unclear. In naïve animals, acute hypoxia evokes increases in phrenic (respiratory) and splanchnic (sympathetic) nerve activities that persist after repeated challenges (long-term facilitation, LTF). In contrast, our studies show that conditioning rats to chronic hypobaric hypoxia (CHH), an environment characteristic of living at high altitude, diminishes the response to hypoxia and attenuates LTF in a time-dependent manner. Phrenic LTF decreases following 7 days of CHH, and both sympathetic and phrenic LTF disappear following 14 days of CHH. Previous studies demonstrated that GABA is released in the brain stem during hypoxia and depresses respiratory activity. Furthermore, the sensitivity of brain stem neurons to GABA is increased following prolonged hypoxia. In this study, we demonstrate that GABA_A receptor expression changes along with the CHH-induced physiological changes. Expression of the GABA_A receptor 4 subunit mRNA increases two-fold in animals conditioned to CHH for 7 days. In addition, de novo expression of and 6, a subunit normally found exclusively in the cerebellum, is observed after 14 days. Consistent with these changes, diazepam-insensitive binding sites, characteristic of GABA_A receptors containing 4 and 6 subunits, increase in the pons. Immunohistochemistry revealed that CHH-induced GABA_A receptor subunit expression is localized in regions of sympathorespiratory control within the pons. Our findings suggest that a GABA_A receptor mediated-mechanism participates in adaptation of the sympathorespiratory system to hypobaric hypoxia.

hypoxia; plasticity; sympathorespiratory network