title: Chronic central serotonin depletion attenuates ventilation and body temperature in young but not adult Tph2 knockout rats.
abstract: Genetic deletion of brain serotonin (5-HT) neurons in mice leads to ventilatory deficits and increased neonatal mortality during development. However, it is unclear if the loss of the 5-HT neurons or the loss of the neurochemical 5-HT led to the observed physiologic deficits. Herein, we generated a mutant rat model with constitutive central nervous system (CNS) 5-HT depletion by mutation of the tryptophan hydroxylase 2 (Tph2) gene in dark agouti (DA(Tph2-/-)) rats. DA(Tph2-/-) rats lacked TPH immunoreactivity and brain 5-HT but retain dopa decarboxylase-expressing raphe neurons. Mutant rats were also smaller, had relatively high mortality (∼50%), and compared with controls had reduced room air ventilation and body temperatures at specific postnatal ages. In adult rats, breathing at rest and hypoxic and hypercapnic chemoreflexes were unaltered in adult male and female DA(Tph2-/-) rats. Body temperature was also maintained in adult DA(Tph2-/-) rats exposed to 4°C, indicating unaltered ventilatory and/or thermoregulatory control mechanisms. Finally, DA(Tph2-/-) rats treated with the 5-HT precursor 5-hydroxytryptophan (5-HTP) partially restored CNS 5-HT and showed increased ventilation (P < 0.05) at a developmental age when it was otherwise attenuated in the mutants. We conclude that constitutive CNS production of 5-HT is critically important to fundamental homeostatic control systems for breathing and temperature during postnatal development in the rat.
authors: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors: Kara
authors: K
authors: Kaplan
authors: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors: Ashley E
authors: AE
authors: Echert
authors: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors: Ben
authors: B
authors: Massat
authors: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin;
authors: Madeleine M
authors: MM
authors: Puissant
authors: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin; and.
authors: Oleg
authors: O
authors: Palygin
authors: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
authors: Aron M
authors: AM
authors: Geurts
authors: Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin; Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin; and mhodges@mcw.edu.
authors: Matthew R
authors: MR
authors: Hodges
mesh_terms: D000818:Animals; D001831:Body Temperature / Q000502:physiology*; D005260:Female; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D011903:Raphe Nuclei / Q000378:metabolism* / Q000502:physiology*; D051381:Rats; D012119:Respiration; D012701:Serotonin / Q000378:metabolism*; D014365:Tryptophan Hydroxylase / Q000235:genetics*; D014691:Ventilation / Q000379:methods
chemical_list: D012701:Serotonin; D014365:Tryptophan Hydroxylase; C504569:tph2 protein, rat
keywords: apnea; chemoreflex; control of breathing; neonate; serotonin