2005), including sustained hypobaric hypoxia (Storz et al. 2010), the circuitry and mechanisms involved in maintaining respiratory control in normoxia are less well characterized. GABAergic signaling is one pathway that has been implicated in respiratory control (Hedner et al. 1981). Many of the actions of γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain, are mediated by pentameric GABAA receptors Inhibitors,research,lifescience,medical assembled from a pool of 19 subunits. The function of these receptors depends on Temozolomide mw subunit composition

(reviewed in Sieghart 2006; Olsen and Sieghart 2009; Uusi-Oukari and Korpi 2010). The most abundantly expressed subunits, α1, β2, and γ2, contribute to synaptic receptors that mediate the rapid, phasic effects of GABA throughout the brain.

Other subunits, including α4, α6, and δ, contribute predominantly to extrasynaptic or perisynaptic receptors that are distributed less widely. These receptors mediate the tonic effects of low concentrations of ambient GABA (Farrant and Nusser 2005; Walker Inhibitors,research,lifescience,medical and Semyanov 2008). Previous studies Inhibitors,research,lifescience,medical demonstrated that sustained exposure to hypobaric hypoxia was accompanied by altered GABAA receptor expression in the pons (Hsieh et al. 2004, 2008), a brainstem region that participates in the control of respiratory behavior (Alheid et al. 2004; Chamberlin 2004; McCrimmon et al. 2004; Smith et al. 2009). The level of the extrasynaptic α4 subunit mRNA rose most rapidly, becoming maximal after 3 days of exposure. Increased Inhibitors,research,lifescience,medical or de novo expression of two other extrasynaptic subunits, δ and α6, was detected after 2 weeks of exposure (Hsieh et al. 2004, 2008). These increases in subunit mRNA expression were accompanied by increases in extrasynaptic receptor number (Hsieh et al. 2008).

The plasticity of extrasynaptic GABAA receptor subunits and receptor Inhibitors,research,lifescience,medical levels in response to a respiratory insult raises the possibility that extrasynaptic receptors are essential for maintaining respiratory function in normoxic conditions. To investigate the role of α4 subunit expression in a normoxic environment, the respiratory patterns, motor and anxiety-like behaviors, and subunit expression were compared in mice lacking this subunit (Gabra4−/−; knockout [KO]) and wild-type (WT) littermates (Gabra4+/+; WT). Studies of respiratory function demonstrated PDK4 that deletion of α4 had no impact on respiratory rate, but reduced the variability of the ventilatory pattern. This physiologic change was accompanied by increased anxiety-like behavior. In addition, compensatory age-dependent changes in the expression of some receptor subunit mRNAs in the pons were observed. While levels of the mRNAs encoding the most abundant synaptic subunits were unaltered in the KO mice, levels of mRNAs encoding extrasynaptic subunits were reduced.