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Transgenic Mice Lacking Serotonin Neurons Have Severe Apnea and High Mortality during Development

2009; Society for Neuroscience; Volume: 29; Issue: 33 Linguagem: Inglês

10.1523/jneurosci.1963-09.2009

1529-2401

Matthew R. Hodges, Mackenzie R. Wehner, Jason Aungst, Jeffrey C. Smith, George B. Richerson,

Sleep and Wakefulness Research

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.