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

Abstract

Abstract Central chemoreception is essential for adjusting breathing to physiological demands, and for maintaining CO 2 and pH homeostasis in the brain. CO 2 -induced ATP release from brainstem astrocytes stimulates breathing. NMDA receptor (NMDAR) antagonism reduces the CO 2 -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 CO 2 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 CO 2 -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.

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