Transgenic mice lacking serotonin neurons have severe apnea and high mortality during development.
Transgenic mice lacking serotonin neurons have severe apnea and high mortality during development.
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DOI：
10.1523/jneurosci.1963-09.2009
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发表时间：
2009-08-19
期刊：
影响因子：
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通讯作者：
Richerson GB
中科院分区：
文献类型：
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作者：
Hodges MR;Wehner M;Aungst J;Smith JC;Richerson GB
中枢5-羟色胺（5-HT）神经元调节许多重要的脑功能，包括呼吸控制。呼吸是否严重依赖于5-HT神经元，或者它们的影响是兴奋性还是抑制性仍然存在争议。在这里，我们发现新生Lmx 1bf/f/p小鼠，选择性缺乏5-羟色胺神经元，显示频繁和严重的呼吸暂停持续长达55秒。这与通气量显著下降至正常值的一半以下有关。这些呼吸异常在出生后期间最为严重，到幼仔2-4周龄时显著改善。尽管有严重的呼吸功能障碍，这些小鼠中的许多存活下来，但围产期死亡率很高，并且那些存活下来的小鼠的生长速度下降，直到呼吸缺陷消退的年龄。与这些在体内的观察结果一致，呼吸输出量显着减少，在分离的脑干脊髓制备新生Lmx 1bf/f/p小鼠，并完全阻断灌注脑制备新生大鼠5-HT 2A和神经激肽1（NK-1）受体的选择性拮抗剂治疗。新生Lmx 1bf/f/p小鼠的排泄缺陷在体外和体内用5-HT 2A和/或NK-1受体激动剂逆转。这些结果表明，新生儿期的呼吸输出严重依赖于5-羟色胺神经元，其通过5-HT 2A和NK-1受体激活向呼吸网络提供兴奋性驱动。这些结果提供了深入了解婴儿猝死综合征（SIDS）的机制，这已与5-HT神经元的异常，心肺控制。
Central serotonin (5-HT) neurons modulate many vital brain functions, including respiratory control. Whether breathing depends critically upon 5-HT neurons, or if their influence is excitatory or inhibitory remains controversial. Here we show that neonatal Lmx1bf/f/p mice, which selectively lack serotonin neurons, display frequent and severe apnea lasting as long as 55 seconds. This was associated with a marked decrease in ventilation to less than half of normal. These respiratory abnormalities were most severe during the post-natal 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 Lmx1bf/f/p mice, and completely blocked in perfused brain preparations from neonatal rats treated with selective antagonists of 5-HT2A and neurokinin 1 (NK-1) receptors. The ventilatory deficits in neonatal Lmx1bf/f/p mice were reversed in vitro and in vivo with agonists of 5-HT2A 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-HT2A and NK-1 receptor activation. These results provide insight into the mechanisms of sudden infant death syndrome (SIDS), which has been associated with abnormalities of 5-HT neurons, and of cardiorespiratory control.