Rats deficient in tryptophan hydroxylase 2 (SSTph2−/− rats) show altered pulmonary neuroendocrine cells (PNECs), reduced resting ventilation and altered hypoxic and hypercapnic chemoreflexes

Abstract

Sudden Infant Death Syndrome (SIDS) is a leading cause of infant mortality from 1–12 months of age, and is thought to occur due to cardiorespiratory failure during sleep. The leading hypothesis as to the causes of SIDS is that abnormalities in the central serotonergic (5HT) system are underlying biological factors contributing to SIDS, but other studies report hypertrophy and hyperplasia of serotonergic lung airway chemosensors called neuroepithelial bodies (NEB) in SIDS. Herein, we tested the hypothesis that rats deficient in tryptophan hydroxylase 2 (TPH2; SSTph2−/− rats), which fail to synthesize brain 5HT, would display NEB hypertrophy and hyperplasia during post‐natal development. We further tested the hypothesis that SSTph2−/− rats would show altered ventilatory chemoreflexes during development, potentially due to altered airway chemoreceptor activity. Cryosections (20μm thick) of inflation fixed lungs were co‐stained for CGRP and Synaptophysin, standard markers of NEBs, and DAPI. Blinded imaging and subsequent analyses indicate a greater number of NEB cells in Tph2−/− rats but a decrease in overall NEB cell size compared to WT rats in 1–2, 12–13, and 18–22 day old groups. These changes correlated with significantly lower weight‐normalized minute ventilation in Tph2−/− rats during room air, hypercapnic, and hypoxic challenges at P12–13, 14–16, and 18–20 day old groups. In conclusion, loss of central serotonin appears to directly or indirectly alter the morphology of peripheral airway 5HT chemosensors.Support or Funding InformationNIH HL R01 122358