Irregularities in breathing pattern during early post-natal life are common but not well understood. Unstable respiratory patterns-for example, apnea of prematurity-are the result of perturbations in the respiratory rhythm generating neural network within the mammalian brainstem. Our current understanding of age-dependent changes suggests that single cell properties and a balance between excitation and inhibition within the local neural network are modulated by endogenous neural modulators like adenosine. Methylxanthines (e.g.caffeine) block adenosine receptors and are typically administered to reduce apneas and breathing irregularity, we seek to understand the mechanism by which adenosine contributes to normal, regular, respiratory pattern generation. Our preliminary data suggest that an interplay between inspiratory neurons and astrocytes within the respiratory rhythm generating/pattern forming network (preBotzinger complex, or pBc) is responsible for stabilizing breathing pattern. We hypothesize that maturational changes in inspiratory neurons and maturation of astrocytes within the pBc during development, promote the emergence of a stable, regular breathing pattern. Adenosine modulates the excitability of both neurons and astrocytes by activating A2 (both A and B) adenosine receptor subtypes. We will use immunohistochemistry to quantify the distribution of neurons and astrocytes during development and then selectively impair astrocytes and quantify changes in inspiratory drive in vitro using electrophysiological methods. Additionally, we will apply A2 adenosine receptor agonists and antagonists to individual neurons and astrocytes during whole-cell patch-clamp recording to evaluate the role that adenosine A2 receptors have in membrane excitation and inhibition. This proposal will determine the mechanisms by which astrocytes and adenosine interact during early maturation, a time of increased susceptibility to life threatening problems of central respiratory rhythm generation.
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