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.
Highlights
Central chemoreception is essential for adjusting breathing to physiological demands, and for maintaining CO2 and pH homeostasis in the brain
After the culture medium was replaced with artificial cerebrospinal fluid, medullary brainstem and cortical astrocytes were exposed to hypercapnic acidosis by switching the gas equilibration from 5 to 10% CO2 in air
A very small increase in L-serine (Fig. 1f) was observed in cortical astrocytes during recovery after hypercapnia. This increase suggests a time-dependent cumulative effect. These results reveal that astrocytes in the medullary brainstem, but not in cortical regions, are able to respond to hypercapnia releasing D-serine and glutamate
Summary
Central chemoreception is essential for adjusting breathing to physiological demands, and for maintaining CO2 and pH homeostasis in the brain. 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. Astrocytes can sense CO2 and H+ in neocortex[5, 6] and act as chemosensory interoceptors in the rat rostral medullary brainstem[4, 7] where they release ATP4, 7 to activate H+-sensitive retrotrapezoid neurons[4, 8,9,10] in response to acidosis or hypercapnia (increased levels of CO2)[4]. Our results reveal that D-serine is released by caudal medullary astrocytes and exerts a respiratory tonic drive and mediates the hypercapnia-induced respiratory response
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