δ-Subunit Containing GABA A Receptors Modulate Respiratory Networks.

Persistent and stable respiratory activity across behavioral states is key to homeostasis. Extrasynaptic δ-subunit containing GABAA receptors (δGABAA Rs) mediate tonic inhibition and regulate network activity. However, the influence of δGABAA Rs on respiratory rhythm and motor outputs is unknown. We manipulated extra-synaptic GABAA receptor function in the preBötzinger Complex (preBötC), a site central to the generation of inspiratory motor activity in mammals. Activation of preBötC δGABAA Rs in anesthetized rats and wild-type mice decreased breathing rate. In δGABAA R knockout (Gabrd-/- ) mice, however, δGABAA Rs 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 δGABAA Rs modulate the respiratory network, which is critical to understand how δGABAA Rs change breathing in pathological conditions affecting extra-synaptic GABAA receptor function such as exposure to anesthetics and neurosteroids.