Maturational changes in neuromodulation of central pathways underlying hypoxic ventilatory response.
The neuromodulator systems mediating the central component of the hypoxic ventilatory response (HVR) during development are complex and diverse. The early component of the HVR is mediated through N-methyl-D-aspartate (NMDA) glutamate receptors in the caudal brainstem. The intracellular downstream signal transductions of the NMDA receptors involve protein kinase C (PKC), neuronal nitric oxide synthase (nNOS) and tyrosine kinase (TK). Activation of NMDA receptors will also lead to activation of the early gene transcription factors including AP-1 (c-fos, c-jun) and NF-kappaB which may play a role in modulation of the subsequent response to hypoxia. NMDA receptors in the caudal brainstem play a critical role in the development of the HVR and increasing dependency on NMDA receptors emerges over time. Similarly, hypoxia-induced PKC, NOS and c-Fos activation in the caudal brainstem is relatively weak in the immature animals, but this activation increases with age and the strength of the response appears to increase concomitantly with the appearance of NMDA expression. Several neurotransmitters including adenosine, gamma-aminobutyric acid (GABA), serotonin and opioids are involved in the late component of the HVR. In addition, the late phase of the HVR is mediated in part through platelet-derived growth factor (PDGF)-beta receptors. PDGF-beta receptor activation is an important contributor of the hypoxic ventilatory depression at all postnatal ages, but its role is more critical in the developing animals. Maturation of these neuromodulators, especially the NMDA and PDGF-beta receptors-mediated pathways, occurs primarily during the early postnatal period. Perturbation of these developmental processes may result in short-term or sustained alterations to the HVR and may also affect neuronal survival during hypoxia.
Simakajornboon
Narong
N
Constance Kaufman Pediatric Pulmonary Research Laboratory, Department of Pediatrics, Tulane University School of Medicine, 1430 Tulane Ave., SL-37 New Orleans, LA, USA. nsimka@tulane.edu
Kuptanon
Teeradej
T
D000818:Animals; D000831:Animals, Newborn; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D007231:Infant, Newborn; D018377:Neurotransmitter Agents / Q000378:metabolism; D012123:Pulmonary Ventilation / Q000502:physiology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012125:Respiratory Center / Q000254:growth & development*; D015398:Signal Transduction / Q000502:physiology*
D018377:Neurotransmitter Agents; D016194:Receptors, N-Methyl-D-Aspartate; D020797:Receptor, Platelet-Derived Growth Factor beta