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Brain hyperserotonemia causes autism-relevant social deficits in mice

BACKGROUND: 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. METHODS: We analyzed behavior and gene expression to unveil the causa...

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Autores principales: Tanaka, Miho, Sato, Atsushi, Kasai, Shinya, Hagino, Yoko, Kotajima-Murakami, Hiroko, Kashii, Hirofumi, Takamatsu, Yukio, Nishito, Yasumasa, Inagaki, Masumi, Mizuguchi, Masashi, Hall, F. Scott, Uhl, George R., Murphy, Dennis, Sora, Ichiro, Ikeda, Kazutaka
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258166/
https://www.ncbi.nlm.nih.gov/pubmed/30498565
http://dx.doi.org/10.1186/s13229-018-0243-3
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author Tanaka, Miho
Sato, Atsushi
Kasai, Shinya
Hagino, Yoko
Kotajima-Murakami, Hiroko
Kashii, Hirofumi
Takamatsu, Yukio
Nishito, Yasumasa
Inagaki, Masumi
Mizuguchi, Masashi
Hall, F. Scott
Uhl, George R.
Murphy, Dennis
Sora, Ichiro
Ikeda, Kazutaka
author_facet Tanaka, Miho
Sato, Atsushi
Kasai, Shinya
Hagino, Yoko
Kotajima-Murakami, Hiroko
Kashii, Hirofumi
Takamatsu, Yukio
Nishito, Yasumasa
Inagaki, Masumi
Mizuguchi, Masashi
Hall, F. Scott
Uhl, George R.
Murphy, Dennis
Sora, Ichiro
Ikeda, Kazutaka
author_sort Tanaka, Miho
collection PubMed
description BACKGROUND: 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. METHODS: We analyzed behavior and gene expression to unveil the causal mechanism of ASD-relevant social deficits using serotonin transporter (Sert) knockout mice. RESULTS: 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. CONCLUSIONS: 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13229-018-0243-3) contains supplementary material, which is available to authorized users.
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spelling pubmed-62581662018-11-29 Brain hyperserotonemia causes autism-relevant social deficits in mice Tanaka, Miho Sato, Atsushi Kasai, Shinya Hagino, Yoko Kotajima-Murakami, Hiroko Kashii, Hirofumi Takamatsu, Yukio Nishito, Yasumasa Inagaki, Masumi Mizuguchi, Masashi Hall, F. Scott Uhl, George R. Murphy, Dennis Sora, Ichiro Ikeda, Kazutaka Mol Autism Research BACKGROUND: 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. METHODS: We analyzed behavior and gene expression to unveil the causal mechanism of ASD-relevant social deficits using serotonin transporter (Sert) knockout mice. RESULTS: 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. CONCLUSIONS: 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13229-018-0243-3) contains supplementary material, which is available to authorized users. BioMed Central 2018-11-26 /pmc/articles/PMC6258166/ /pubmed/30498565 http://dx.doi.org/10.1186/s13229-018-0243-3 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Tanaka, Miho
Sato, Atsushi
Kasai, Shinya
Hagino, Yoko
Kotajima-Murakami, Hiroko
Kashii, Hirofumi
Takamatsu, Yukio
Nishito, Yasumasa
Inagaki, Masumi
Mizuguchi, Masashi
Hall, F. Scott
Uhl, George R.
Murphy, Dennis
Sora, Ichiro
Ikeda, Kazutaka
Brain hyperserotonemia causes autism-relevant social deficits in mice
title Brain hyperserotonemia causes autism-relevant social deficits in mice
title_full Brain hyperserotonemia causes autism-relevant social deficits in mice
title_fullStr Brain hyperserotonemia causes autism-relevant social deficits in mice
title_full_unstemmed Brain hyperserotonemia causes autism-relevant social deficits in mice
title_short Brain hyperserotonemia causes autism-relevant social deficits in mice
title_sort brain hyperserotonemia causes autism-relevant social deficits in mice
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258166/
https://www.ncbi.nlm.nih.gov/pubmed/30498565
http://dx.doi.org/10.1186/s13229-018-0243-3
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