Persistent and stable respiratory activity across behavioral states is key to homeostasis. Extrasynaptic δ-subunit containing GABA_A receptors(δGABA_ARs) mediate tonic inhibition and regulate network activity. However, the influence of δGABA_ARs on respiratory rhythm and motor outputs is unknown. We manipulated extra-synaptic GABA_A receptor function in the preBötzinger Complex (preBötC), a site central to the generation of inspiratory motor activity in mammals. Activation of preBötC δGABA_ARs in anesthetized rats and wild-type mice decreased breathing rate. In δGABA_AR knockout (Gabrd ^-/-) mice, however, δGABA_ARs activation had no effect on breathing rate. We then found that during active wakefulness associated with behaviors and movements, diaphragm activation was higher in the Gabrd ^-/- compared to wild-type mice, but not in other states. These findings identify that δGABA_ARs modulate the respiratory network, which is critical to understand how δGABA_ARs change breathing in pathological conditions affecting extra-synaptic GABA_A receptor function such as exposure to anesthetics and neurosteroids.

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