Serotonin transporter knockout mice have a reduced ventilatory response to hypercapnia (predominantly in males) but not to hypoxia.
Medullary serotonergic (5-HT) neurons are implicated in central chemoreception and 5-HT abnormalities are present in many cases of the sudden infant death syndrome (SIDS). Mice with a targeted disruption of the serotonin transporter (5-HTT) develop in the presence of excess 5-HT in brain extracellular fluid (ECF). As adults they exhibit reduced 5-HT neuron activity and 5-HT1A receptor binding with varying changes in postsynaptic 5-HT receptor function. They exhibit behavioural phenotypes (anxiety, reduced aggression) but little is known about their control of breathing. We show that conscious adult male and female 5-HTT knockout mice breathing air at room temperature have a higher resting (.)VO2, breathing frequency and (.)VE but a normal body temperature and (.)VE/ (.)VO2 ratio (the ventilatory equivalent) compared to wild-type (WT) controls. In hypercapnia, there is a reduced ventilatory response (expressed as the (.)VE/ (.)VO2 ratio) that is much more prominent in males (-68%) than females (-22%). In hypoxia, both males and females exhibit a higher (.)VE, (.)VO2 and body temperature but their (.)VE/ (.)VO2 ratio is normal. We conclude that 5-HTT knockout mice have a diminished function of the medullary 5-HT system, which is manifest most remarkably in a substantial loss of CO2 sensitivity predominantly in males. This finding supports the importance of medullary 5-HT neurons in central chemoreception. Females either rely less on 5-HT neurons in chemoreception or adapt more readily to the loss of 5-HT function. This genetic model allows examination of the role of excess 5-HT in ECF in the development of the control of breathing and central chemoreception, which may be pertinent to SIDS.
Li
Aihua
A
Department of Physiology, Dartmouth Medical School, Lebanon, NH 03756-0001, USA. aihua.li@dartmouth.edu
Nattie
Eugene
E
D000818:Animals; D005260:Female; D006935:Hypercapnia / Q000503:physiopathology*; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D008526:Medulla Oblongata / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012123:Pulmonary Ventilation; D015656:Respiratory Mechanics; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D012737:Sex Factors
D050486:Serotonin Plasma Membrane Transport Proteins