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首页> 外文期刊>The Journal of Clinical Investigation: The Official Journal of the American Society for Clinical Investigation >Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function
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Serotonin transporter variant drives preventable gastrointestinal abnormalities in development and function

机译：血清素转运蛋白变体驱动可预防的胃肠道发育和功能异常

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摘要

Autism spectrum disorder (ASD) is an increasingly common behavioral condition that frequently presents with gastrointestinal (GI) disturbances. It is not clear, however, how gut dysfunction relates to core ASD features. Multiple, rare hyperfunctional coding variants of the serotonin (5-HT) transporter (SERT, encoded by SLC6A4) have been identified in ASD. Expression of the most common SERT variant (Ala56) in mice increases 5-HT clearance and causes ASD-like behaviors. Here, we demonstrated that Ala56-expressing mice display GI defects that resemble those seen in mice lacking neuronal 5-HT. These defects included enteric nervous system hypoplasia, slow GI transit, diminished peristaltic reflex activity, and proliferation of crypt epithelial cells. An opposite phenotype was seen in SERT-deficient mice and in progeny of WT dams given the SERT antagonist fluoxetine. The reciprocal phenotypes that resulted from increased or decreased SERT activity support the idea that 5-HT signaling regulates enteric neuronal development and can, when disturbed, cause long-lasting abnormalities of GI function. Administration of a 5-HT 4 agonist to Ala56 mice during development prevented Ala56-associated GI perturbations, suggesting that excessive SERT activity leads to inadequate 5-HT4-mediated neurogenesis. We propose that deficient 5-HT signaling during development may contribute to GI and behavioral features of ASD. The consequences of therapies targeting SERT during pregnancy warrant further evaluation.
机译：自闭症谱系障碍 （ASD） 是一种越来越常见的行为状况，经常表现为胃肠道 （GI） 紊乱。然而，目前尚不清楚肠道功能障碍与ASD核心特征的关系。在 ASD 中已发现 5-羟色胺 （5-HT） 转运蛋白（SERT，由 SLC6A4 编码）的多种罕见的超功能编码变体。小鼠中最常见的 SERT 变体 （Ala56） 的表达增加了 5-HT 清除率并引起 ASD 样行为。在这里，我们证明了表达Ala56的小鼠表现出类似于缺乏神经元5-HT的小鼠的GI缺陷。这些缺陷包括肠神经系统发育不全、胃肠道转运缓慢、蠕动反射活动减弱和隐窝上皮细胞增殖。在给予 SERT 拮抗剂氟西汀的 SER 缺陷小鼠和 WT 大坝的后代中观察到相反的表型。由SERT活性增加或降低引起的相互表型支持5-HT信号转导调节肠道神经元发育的观点，并且在受到干扰时会导致胃肠道功能的长期异常。在发育过程中对 Ala56 小鼠施用 5-HT 4 激动剂可防止 Ala56 相关的 GI 扰动，表明过度的 SERT 活性导致 5-HT4 介导的神经发生不足。我们认为，发育过程中缺乏的 5-HT 信号可能导致 ASD 的胃肠道和行为特征。妊娠期靶向 SERT 治疗的后果值得进一步评估。

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