Medullary 5-HT neurons: Switch from tonic respiratory drive to chemoreception during postnatal development.
Serotonin (5-HT) neurons contribute to respiratory chemoreception in adult mice, but it is unclear whether they play a similar role in neonatal mice. We studied breathing during development in Lmx1bf/f/pmice, which lack 5-HT neurons. From postnatal days 1-7 (P1-P7), ventilation of Lmx1bf/f/pmice breathing room air was 50% of WT mice (p<0.001). By P12, baseline ventilation increased to a level equal to WT mice. In contrast, the hypercapnic ventilatory response (HCVR) of neonatal Lmx1bf/f/pand WT mice was equal to each other, but were both much less than adult WT mice. By P21 the HCVR of WT mice increased to near adult levels, but the HCVR of Lmx1bf/f/pmice had not changed, and was 42% less than WT mice. Primary cell cultures were prepared from the ventromedial medulla of neonatal mice, and patch-clamp recordings were made from neurons identified as serotonergic by expression of a reporter gene. In parallel with developmental changes of the HCVR in vivo, 5-HT neurons had little chemosensitivity to acidosis until 12days in vitro (DIV), after which their response increased to reach a plateau around 25 DIV. Neonatal Lmx1bf/f/pmice displayed high mortality and decreased growth rate, and this worsened in hypoxia. Mortality was decreased in hyperoxia. These results indicate that maturation of 5-HT neurons contributes to development of respiratory CO2/pH chemoreception during the first few weeks of life in mice in vivo. A defect in the 5-HT system in early postnatal life decreases survival due in part to hypoxia.
Department of Neurology, Yale University, New Haven, CT 06510, United States; Department of Neurology, University of Iowa, Iowa City, IA 52242, United States.
Veronica J
VJ
Cerpa
Department of Neurology, Yale University, New Haven, CT 06510, United States; Department of Neurology, University of Iowa, Iowa City, IA 52242, United States.
Yuanming
Y
Wu
Department of Neurology, University of Iowa, Iowa City, IA 52242, United States. Electronic address: eduardo-bravo@uiowa.edu.
Eduardo
E
Bravo
Department of Neurology, University of Iowa, Iowa City, IA 52242, United States.
Frida A
FA
Teran
Department of Neurology, Yale University, New Haven, CT 06510, United States.
Rachel S
RS
Flynn
Department of Neurology, Yale University, New Haven, CT 06510, United States; Department of Neurology, University of Iowa, Iowa City, IA 52242, United States; Department of Molecular Physiology & Biophysics, University of Iowa, Iowa City, IA 52242, United States; Veterans Affairs Medical Center, Iowa City, IA 52242, United States.
George B
GB
Richerson
D000138:Acidosis / Q000503:physiopathology; D000200:Action Potentials / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D002245:Carbon Dioxide / Q000378:metabolism; D002478:Cells, Cultured; D002628:Chemoreceptor Cells / Q000502:physiology*; D000860:Hypoxia / Q000401:mortality / Q000503:physiopathology; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008526:Medulla Oblongata / Q000254:growth & development* / Q000502:physiology* / Q000503:physiopathology; D008822:Mice, Transgenic; D018408:Patch-Clamp Techniques; D010993:Plethysmography, Whole Body; D012119:Respiration; D059326:Serotonergic Neurons / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
C112149:LIM homeobox transcription factor 1 beta; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors; D002245:Carbon Dioxide; D012701:Serotonin
Lmx1b; chemoreception; respiratory; serotonin