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 GABA(A) receptors (δGABA(A)Rs) mediate tonic inhibition and regulate network activity. However, the influence of δGABA(A)Rs 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(A)Rs in anesthetized rats and wild-type mice decreased breathing rate. In δGABA(A)R knockout (Gabrd (−/−)) mice, however, δGABA(A)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 δGABA(A)Rs modulate the respiratory network, which is critical to understand how δGABA(A)Rs change breathing in pathological conditions affecting extra-synaptic GABA(A) receptor function such as exposure to anesthetics and neurosteroids.