Transgenic mice lacking serotonin neurons have severe apnea and high mortality during development.
Central serotonin (5-HT) neurons modulate many vital brain functions, including respiratory control. Whether breathing depends critically on 5-HT neurons, or whether their influence is excitatory or inhibitory, remains controversial. Here we show that neonatal Lmx1b(flox/flox;ePet-Cre/+) mice (also called Lmx1b(f/f/p) mice), which selectively lack serotonin neurons, display frequent and severe apnea lasting as long as 55 s. This was associated with a marked decrease in ventilation to less than one-half of normal. These respiratory abnormalities were most severe during the postnatal period, markedly improving by the time the pups were 2-4 weeks old. Despite the severe breathing dysfunction, many of these mice survived, but there was a high perinatal mortality, and those that survived had a decrease in growth rate until the age at which the respiratory defects resolved. Consistent with these in vivo observations, respiratory output was markedly reduced in isolated brainstem-spinal cord preparations from neonatal Lmx1b(f/f/p) mice and completely blocked in perfused brain preparations from neonatal rats treated with selective antagonists of 5-HT(2A) and neurokinin 1 (NK-1) receptors. The ventilatory deficits in neonatal Lmx1b(f/f/p) mice were reversed in vitro and in vivo with agonists of 5-HT(2A) and/or NK-1 receptors. These results demonstrate that ventilatory output in the neonatal period is critically dependent on serotonin neurons, which provide excitatory drive to the respiratory network via 5-HT(2A) and NK-1 receptor activation. These findings provide insight into the mechanisms of sudden infant death syndrome, which has been associated with abnormalities of 5-HT neurons and of cardiorespiratory control.
Hodges
Matthew R
MR
Departments of Neurology and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA. matthew.hodges@yale.edu
Wehner
Mackenzie
M
Aungst
Jason
J
Smith
Jeffrey C
JC
Richerson
George B
GB
D000818:Animals; D000831:Animals, Newborn; D001049:Apnea / Q000235:genetics / Q000378:metabolism* / Q000401:mortality*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015656:Respiratory Mechanics / Q000235:genetics; D012701:Serotonin / Q000172:deficiency* / Q000235:genetics
D012701:Serotonin
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