Our long term goal is to understand how plasticity of the GABAA receptor, a pentameric ligand-gated ion channel, participates in maintaining CNS function. The proposed studies will test the hypothesis that changes in expression of two GABAA receptor subunits, ?6 and ?4, participate in mediating the response to reduced oxygen. In previous studies on adult rats we found that sustained hypobaric hypoxia selectively triggers de novo ?6 subunit mRNA and protein expression and increases ?4 and ? subunit mRNA levels in the pons, a brainstem region involved in maintaining homeostasis. Induction of ?6 expression is notable because this subunit normally is found only in the postnatal cerebellum. More importantly, ?6 or ?4, in other brain regions, coassemble with ? in extrasynaptic GABAA receptors that mediate the response to basal levels of GABA, i.e., tonic inhibition. To investigate the role of GABAA receptor plasticity in the response to sustained hypoxia, molecular, histological, and physiologic studies on wild-type and ?6 or ?4 subunit-deficient mice are proposed to: 1) Determine how sustained hypobaric hypoxia alters GABAA receptor subunit mRNA expression in the brainstem of mice maintained in control or hypoxic conditions using qRT-PCR;2) Locate cells that express the ?6 and ?4 subunit polypeptides and determine whether changes in subunit levels alter receptor number in the brainstem following sustained hypoxia using immunohistochemical and biochemical approaches;and 3) Determine the importance of ?4 or ?6 GABAA receptor subunit expression for the ventilatory response to sustained hypoxia using whole-body plethysmography. Findings from these studies will begin to define molecular mechanisms used in adapting to reduced oxygen, a stress that occurs physiologically at high altitude and in several pathological conditions, including chronic obstructive pulmonary diseases. Specifically, the proposed studies will provide insight into the contribution of GABAA receptor plasticity. Our findings will lay the groundwork for studies aimed at understanding the circuitry involved in maintaining brain function. Identifying the molecular machinery involved in the response to sustained hypoxia is an essential first step for creating novel therapeutic approaches to combat a variety of potentially life-threatening conditions. PUBLIC HEALTH RELEVANCE The ability of the mature brain to adapt to environmental stress is required for survival. Our recent findings raise the possibility that plasticity of the GABAA receptor, which mediates the actions of the major inhibitory neurotransmitter in the brain, participates in mediating adaptation to hypoxia. Oxygen deprivation is a stress that occurs during many physiological and pathological conditions, including life at high altitude and chronic obstructive pulmonary diseases. The goal of our proposed studies is to demonstrate that changes in the expression of specific GABAA receptor subunits are required for adaptation to hypoxia. Identifying the molecular machinery involved in the response to hypoxia is an essential first step for creating novel therapeutic approaches to combat a variety of potentially life-threatening situations.