D-serine released by astrocytes in brainstem regulates breathing response to CO2 levels

Central chemoreception is essential for adjusting breathing to physiological demands, and for maintaining CO2 and pH homeostasis in the brain. CO2-induced ATP release from brainstem astrocytes stimulates breathing. NMDA receptor (NMDAR) antagonism reduces the CO2-induced hyperventilation by unknown mechanisms. Here we show that astrocytes in the mouse caudal medullary brainstem can synthesize, store, and release d-serine, an agonist for the glycine-binding site of the NMDAR, in response to elevated CO2 levels. We show that systemic and raphe nucleus d-serine administration to awake, unrestrained mice increases the respiratory frequency. Application of d-serine to brainstem slices also increases respiratory frequency, which was prevented by NMDAR blockade. Inhibition of d-serine synthesis, enzymatic degradation of d-serine, or the sodium fluoroacetate-induced impairment of astrocyte functions decrease the basal respiratory frequency and the CO2-induced respiratory response in vivo and in vitro. Our findings suggest that astrocytic release of d-serine may account for the glutamatergic contribution to central chemoreception.