Cerebral erythropoietin regulates the respiratory control system during early postnatal life

Abstract

Apart from its role in neuroprotection, erythropoietin (Epo) synthesized by neurons and astrocytes modulates the respiratory control system in adult mice. However, the impact of Epo in the regulation of the neural control of breathing during the postnatal development remains unknown. Here we use a transgenic mouse line (Tg21) constitutively overexpressing human Epo in brain to investigate whether Epo interacts with the brainstem centers associated with respiration during postnatal life. Our immunohistochemical analysis revealed that Epo and Epo receptor (EpoR) are expressed in the main central respiratory nuclei at 1, 4, 7, 10, 15 and 21 days of age. Furthermore, by using antibodies to choline acetyltranferase (ChAT), somatostatin (SST) and neurokinin receptor 1 (NK1), EpoR was localized to the pre‐Bötzinger complex nucleus at all studied postnatal days. Whole body phtethysmography technique was used to evaluate basal ventilation and ventilatory response to hypoxia at 10% and 6% O2. Compared to wild type animals, Tg21 mice showed improved hypoxic ventilation (both at 10% and 6% O2) at postnatal days 15 and 21, but not 7 and 10. These results are in line with data obtained by radioimmunoassay, showing that overexpression of Epo in transgenic mice brains dramatically increases after 10 days of postnatal life. These results imply that cerebral Epo plays a key‐regulating role in the neural control of breathing in a period in which the central respiratory network undergoes full development and maturation.Source of research support is Molly Towell Perinatal Research Foundation (MTPRF).