11 Data figures and text NCOMMS-16-21368C.xlsx

Data used in figures and text in the paper NCOMMS-16-21368C entitled:<br>D-serine released by astrocytes in the brainstem regulates the breathing response to CO₂ levels<br>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 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 CO₂levels. We show that systemic and raphe nucleus D-serine administration to awake, unrestrained mice increase the respiratory frequency (fR). Application of D-serine to brainstem slices also increases fR, 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 fR and the CO₂-induced respiratory response <i>in vivo</i> and <i>in vitro</i>. Our findings suggest that astrocytic release of D-serine may account for the glutamatergic contribution to central chemoreception.<br><br>