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

S. Beltrán-Castillo, M. J. Olivares, R. A. Contreras, G. Zúñiga, I. Llona, R. von Bernhardi () and J. L. Eugenín ()
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S. Beltrán-Castillo: Universidad de Santiago de Chile, USACH
M. J. Olivares: Universidad de Santiago de Chile, USACH
R. A. Contreras: Universidad de Santiago de Chile, USACH
G. Zúñiga: Universidad de Santiago de Chile, USACH
I. Llona: Universidad de Santiago de Chile, USACH
R. von Bernhardi: Pontificia Universidad Católica de Chile
J. L. Eugenín: Universidad de Santiago de Chile, USACH

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-00960-3

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