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Brain hyperserotonemia causes autism-relevant social deficits in mice
Molecular Autism ( IF 6.2 ) Pub Date : 2018-11-26 , DOI: 10.1186/s13229-018-0243-3
Miho Tanaka , Atsushi Sato , Shinya Kasai , Yoko Hagino , Hiroko Kotajima-Murakami , Hirofumi Kashii , Yukio Takamatsu , Yasumasa Nishito , Masumi Inagaki , Masashi Mizuguchi , F. Scott Hall , George R. Uhl , Dennis Murphy , Ichiro Sora , Kazutaka Ikeda

Hyperserotonemia in the brain is suspected to be an endophenotype of autism spectrum disorder (ASD). Reducing serotonin levels in the brain through modulation of serotonin transporter function may improve ASD symptoms. We analyzed behavior and gene expression to unveil the causal mechanism of ASD-relevant social deficits using serotonin transporter (Sert) knockout mice. Social deficits were observed in both heterozygous knockout mice (HZ) and homozygous knockout mice (KO), but increases in general anxiety were only observed in KO mice. Two weeks of dietary restriction of the serotonin precursor tryptophan ameliorated both brain hyperserotonemia and ASD-relevant social deficits in Sert HZ and KO mice. The expression of rather distinct sets of genes was altered in Sert HZ and KO mice, and a substantial portion of these genes was also affected by tryptophan depletion. Tryptophan depletion in Sert HZ and KO mice was associated with alterations in the expression of genes involved in signal transduction pathways initiated by changes in extracellular serotonin or melatonin, a derivative of serotonin. Only expression of the AU015836 gene was altered in both Sert HZ and KO mice. AU015836 expression and ASD-relevant social deficits normalized after dietary tryptophan restriction. These findings reveal a Sert gene dose-dependent effect on brain hyperserotonemia and related behavioral sequelae in ASD and a possible therapeutic target to normalize brain hyperserotonemia and ASD-relevant social deficits.

中文翻译:

脑高血清素血症导致小鼠自闭症相关的社会缺陷

大脑中的高血清素被怀疑是自闭症谱系障碍(ASD)的一种内表型。通过调节血清素转运蛋白功能降低大脑中的血清素水平可以改善ASD症状。我们分析了行为和基因表达,以揭示使用5-羟色胺转运蛋白(Sert)基因敲除小鼠的ASD相关性社会缺陷的病因机制。在杂合基因敲除小鼠(HZ)和纯合基因敲除小鼠(KO)中均观察到社交缺陷,但仅在KO小鼠中观察到一般性焦虑增加。血清素前体色氨酸的饮食限制两周改善了Sert HZ和KO小鼠的脑部高血清素血症和与ASD相关的社会缺陷。在Sert HZ和KO小鼠中,相当不同的基因集的表达发生了变化,这些基因的很大一部分也受到色氨酸耗竭的影响。Sert HZ和KO小鼠中的色氨酸耗竭与细胞外5-羟色胺或褪黑素(一种5-羟色胺的衍生物)的变化引发的信号转导通路中涉及的基因表达的改变有关。在Sert HZ和KO小鼠中仅AU015836基因的表达发生了改变。饮食色氨酸限制后,AU015836的表达和与ASD相关的社会缺陷得以恢复正常。这些发现揭示了Sert基因对ASD中脑高血清素血症和相关行为后遗症的剂量依赖性作用,以及使脑高血清素血症和与ASD相关的社会缺陷正常化的可能治疗靶标。Sert HZ和KO小鼠中的色氨酸耗竭与细胞外5-羟色胺或褪黑素(一种5-羟色胺的衍生物)的变化引发的信号转导通路中涉及的基因表达的改变有关。在Sert HZ和KO小鼠中只有AU015836基因的表达发生了改变。饮食色氨酸限制后,AU015836的表达和与ASD相关的社会缺陷得以恢复正常。这些发现揭示了Sert基因对ASD中脑高血清素血症和相关行为后遗症的剂量依赖性作用,以及使脑高血清素血症和与ASD相关的社会缺陷正常化的可能治疗靶标。Sert HZ和KO小鼠中的色氨酸耗竭与细胞外5-羟色胺或褪黑素(一种5-羟色胺的衍生物)的变化引发的信号转导通路中涉及的基因表达的改变有关。在Sert HZ和KO小鼠中仅AU015836基因的表达发生了改变。饮食色氨酸限制后,AU015836的表达和与ASD相关的社会缺陷得以恢复正常。这些发现揭示了Sert基因对ASD中脑高血清素血症和相关行为后遗症的剂量依赖性作用,以及使脑高血清素血症和与ASD相关的社会缺陷正常化的可能治疗靶标。饮食色氨酸限制后,AU015836的表达和与ASD相关的社会缺陷得以恢复正常。这些发现揭示了Sert基因对ASD中脑高血清素血症和相关行为后遗症的剂量依赖性作用,以及使脑高血清素血症和与ASD相关的社会缺陷正常化的可能治疗靶标。饮食色氨酸限制后,AU015836的表达和与ASD相关的社会缺陷得以恢复正常。这些发现揭示了Sert基因对ASD中脑高血清素血症和相关行为后遗症的剂量依赖性作用,以及使脑高血清素血症和与ASD相关的社会缺陷正常化的可能治疗靶标。
更新日期:2018-11-26
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