Fetal, maternal, and placental sources of serotonin and new implications for developmental programming of the brain.
Fetal, maternal, and placental sources of serotonin and new implications for developmental programming of the brain.
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DOI：
10.1016/j.neuroscience.2011.10.005
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发表时间：
2011-12-01
期刊：
影响因子：
3.3
通讯作者：
Levitt, P.
中科院分区：
文献类型：
--
作者：
Bonnin, A.;Levitt, P.
越来越多的证据表明，5-羟色胺（5-HT）有助于儿童和成人发病的精神疾病的发展规划。这被认为是通过5-HT调节细胞增殖、迁移和电路布线等发育过程的能力而发生的。例如，对小鼠的遗传研究表明，在出生前和出生后发育的有限时期内，5-HT信号的中断会导致长期的行为异常，例如成年后焦虑增加。成年人焦虑的发育编程可以通过单一5-HT受体[5-HT 1A]的短暂敲低或通过短暂发育暴露于特定的5-羟色胺再摄取抑制剂（SSRIs）来触发。最近发现5-HT在子宫内胎儿前脑布线中的作用，表明5-HT信号中断可能对脑功能产生长期影响的潜在机制。5-HT信号通过两种受体（htr 1b/1d; 5-HT 1B/1D）在体外将丘脑轴突对netrin-1的反应从吸引转变为排斥。在体内有针对性地破坏5-HT 1B/1D受体在背侧丘脑中的表达导致内囊和皮质中的异常丘脑皮质轴突（TCA）通路。因此，通过激活的5-HT受体的数量和/或类型的5-HT信号传导水平对于正常的大脑发育是至关重要的。5-HT受体激活的浓度可能是正常脑发育的另一个重要参数。我们最近证明，胎儿前脑选择性地积累胎盘来源的5-HT在最初的轴突生长期。这些数据表明，胎儿大脑中的某些发育回路在其最初的个体发育过程中对胎盘5-HT敏感，这可能受到遗传和环境干扰的影响，这些干扰已知会增加精神疾病的风险。5-HT信号在胎儿脑布线中的作用和胎盘代谢在5-HT介导的胎儿编程中的潜在重要性将在下文讨论。
Accumulating evidences suggest that serotonin (5-HT) contributes to the developmental programming of childhood- and adult-onset mental illnesses. This is thought to occur through the capacity of 5-HT to modulate developmental processes such as cell proliferation, migration and circuit wiring. For instance, genetic studies in mice show that disruption of 5-HT signaling during a restricted period of pre- and postnatal development results in long-term behavioral abnormalities such as increased anxiety in adulthood. The developmental programming of adult anxiety can be triggered either by a transient knockdown of a single 5-HT receptor [5-HT1A, ] or by a transient developmental exposure to specific serotonin reuptake inhibitors (SSRIs). The recent discovery of a role for 5-HT in fetal forebrain wiring in utero suggests a potential mechanism by which 5-HT signaling disruption can have long-term consequences on brain function. 5-HT signaling through two receptors (htr1b/1d; 5-HT1B/1D) switches the response of thalamic axons to netrin-1 from attraction to repulsion in vitro. Targeted disruption in vivo of 5-HT1B/1D receptors expression in the dorsal thalamus led to abnormal thalamocortical axons (TCAs) pathways in the internal capsule and cortex. Thus, the level 5-HT signaling through the number and/or type of 5-HT receptors activated is critical for normal brain development. The concentration of 5-HT available for receptors activation is likely another important parameter for normal brain development. We recently demonstrated that the fetal forebrain selectively accumulates placenta-derived 5-HT during the initial axon growth period. These data suggest that certain developing circuits in the fetal brain are sensitive to placental 5-HT during their initial ontogeny, which could be impacted by both genetic and environmental disturbances that are known to increase risk for mental illnesses. The role of 5-HT signaling in fetal brain wiring and the potential importance of placental metabolism in 5-HT-mediated fetal programing are discussed below.
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