N-methyl-D-aspartate receptor expression in the nucleus tractus solitarii and maturation of hypoxic ventilatory response in the rat

Ventilatory responses to hypoxia are critically dependent on the activation of N-methyl-D-aspartate (NMDA) glutamate receptors in adult rats. To inves tigate the role of NMDA receptors during development, we measured minute ve ntilation (VE) in 5-d, 10-d, and 15-d-old intact, freely behaving rat pups, using whole-body plethysmography during breathing of room air (RA), during hypoxia (10% O-2), and during hypercapnia (5% CO2), both before and after administration of the NMDA receptor antagonist MK-801 (1 mg/kg intraperiton eally). MK-801 did not affect (V) over dotE in RA in the younger animals, b ut increased both (V) over dotE and respiratory frequency in the 15-d-old r ats. Similarly, (V) over dotE responses to hypoxia were unchanged from cont rol values in young animals, whereas (V) over dotE respones in 15-d-old rat s showed significant attenuation under hypoxic conditions. In contrast, hyp ercapnic ventilatory responses were not altered by administration of MK-801 to rats at any age. To further examine the topographic distribution patter ns of NMDA receptor-positive neurons in the caudal brainstem and their recr uitment during hypoxia, we performed immunostaining for NMDA receptor subun it NR1 and c-fos after exposing rat pups at postnatal ages of 2 d, 5 d, 10 d, and 20 d and adult rats to either RA or 10% O-2 for 3 h. With advancing postnatal age, NR1 expression increased in the nucleus tractus solitarii (n TS), whereas it decreased in the hypoglossal nucleus. Hypoxic exposure was associated with increased c-fos expression in the nTS at all postnatal ages , with a marked increase occurring in greater than or equal to 10-d-old ani mals. Similarly, the density of c-fos-NR1 double-labeled neurons during hyp oxia progressively increased with maturation. We conclude that NMDA glutama te receptor expression in the caudal brainstem undergoes postnatal maturati on that closely parallels the development of the hypoxic ventilatory respon se in the rat.