Prenatal nutritional intervention reduces autistic-like behavior rates among mthfr-deficient mice

© 2019 Frontiers Media S.A.. All rights reserved. The causes and contributing factors of autism spectrum disorders (ASD) are poorly understood. One gene associated with increased risk for ASD is methylenetetrahydrofolate-reductase (MTHFR), which encodes a key enzyme in one carbon (C1) metabolism. Th...

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Main Authors: Ayelet Orenbuch, Keren Fortis, Siraphat Taesuwan, Raz Yaffe, Marie A. Caudill, Hava M. Golan
Format: Journal
Published: 2019
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spelling th-cmuir.6653943832-658442019-08-05T04:42:17Z Prenatal nutritional intervention reduces autistic-like behavior rates among mthfr-deficient mice Ayelet Orenbuch Keren Fortis Siraphat Taesuwan Raz Yaffe Marie A. Caudill Hava M. Golan Neuroscience © 2019 Frontiers Media S.A.. All rights reserved. The causes and contributing factors of autism spectrum disorders (ASD) are poorly understood. One gene associated with increased risk for ASD is methylenetetrahydrofolate-reductase (MTHFR), which encodes a key enzyme in one carbon (C1) metabolism. The MTHFR 677C > T polymorphism reduces the efficiency of methyl group production with possible adverse downstream effects on gene expression. In this study, the effects of prenatal and/or postnatal diets enriched in C1 nutrients on ASD-like behavior were evaluated in Mthfr-deficient mice. Differences in intermediate pathways between the mice with and without ASD-like behaviors were tested. The findings indicate that maternal and offspring Mthfr deficiency increased the risk for an ASD-like phenotype in the offspring. The risk of ASD-like behavior was reduced in Mthfr-deficient mice supplemented with C1 nutrients prenatally. Specifically, among offspring of Mthfr+/-dams, prenatal diet supplementation was protective against ASD-like symptomatic behavior compared to the control diet with an odds ratio of 0.18 (CI:0.035, 0.970). Changes in major C1 metabolites, such as the ratios between betaine/choline and SAM/SAH in the cerebral-cortex, were associated with ASD-like behavior. Symptomatic mice presenting ASD-like behavior showed decreased levels of GABA pathway proteins such as GAD65/67 and VGAT and altered ratios of the glutamate receptor subunits GluR1/GluR2 in males and NR2A/NR2B in females. The altered ratios, in turn, favor receptor subunits with higher sensitivity to neuronal activity. Our study suggests that MTHFR deficiency can increase the risk of ASD-like behavior in mice and that prenatal dietary intervention focused on MTHFR genotypes can reduce the risk of ASD-like behavior. 2019-08-05T04:42:17Z 2019-08-05T04:42:17Z 2019-01-01 Journal 1662453X 16624548 2-s2.0-85068570220 10.3389/fnins.2019.00383 https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85068570220&origin=inward http://cmuir.cmu.ac.th/jspui/handle/6653943832/65844
institution Chiang Mai University
building Chiang Mai University Library
country Thailand
collection CMU Intellectual Repository
topic Neuroscience
spellingShingle Neuroscience
Ayelet Orenbuch
Keren Fortis
Siraphat Taesuwan
Raz Yaffe
Marie A. Caudill
Hava M. Golan
Prenatal nutritional intervention reduces autistic-like behavior rates among mthfr-deficient mice
description © 2019 Frontiers Media S.A.. All rights reserved. The causes and contributing factors of autism spectrum disorders (ASD) are poorly understood. One gene associated with increased risk for ASD is methylenetetrahydrofolate-reductase (MTHFR), which encodes a key enzyme in one carbon (C1) metabolism. The MTHFR 677C > T polymorphism reduces the efficiency of methyl group production with possible adverse downstream effects on gene expression. In this study, the effects of prenatal and/or postnatal diets enriched in C1 nutrients on ASD-like behavior were evaluated in Mthfr-deficient mice. Differences in intermediate pathways between the mice with and without ASD-like behaviors were tested. The findings indicate that maternal and offspring Mthfr deficiency increased the risk for an ASD-like phenotype in the offspring. The risk of ASD-like behavior was reduced in Mthfr-deficient mice supplemented with C1 nutrients prenatally. Specifically, among offspring of Mthfr+/-dams, prenatal diet supplementation was protective against ASD-like symptomatic behavior compared to the control diet with an odds ratio of 0.18 (CI:0.035, 0.970). Changes in major C1 metabolites, such as the ratios between betaine/choline and SAM/SAH in the cerebral-cortex, were associated with ASD-like behavior. Symptomatic mice presenting ASD-like behavior showed decreased levels of GABA pathway proteins such as GAD65/67 and VGAT and altered ratios of the glutamate receptor subunits GluR1/GluR2 in males and NR2A/NR2B in females. The altered ratios, in turn, favor receptor subunits with higher sensitivity to neuronal activity. Our study suggests that MTHFR deficiency can increase the risk of ASD-like behavior in mice and that prenatal dietary intervention focused on MTHFR genotypes can reduce the risk of ASD-like behavior.
format Journal
author Ayelet Orenbuch
Keren Fortis
Siraphat Taesuwan
Raz Yaffe
Marie A. Caudill
Hava M. Golan
author_facet Ayelet Orenbuch
Keren Fortis
Siraphat Taesuwan
Raz Yaffe
Marie A. Caudill
Hava M. Golan
author_sort Ayelet Orenbuch
title Prenatal nutritional intervention reduces autistic-like behavior rates among mthfr-deficient mice
title_short Prenatal nutritional intervention reduces autistic-like behavior rates among mthfr-deficient mice
title_full Prenatal nutritional intervention reduces autistic-like behavior rates among mthfr-deficient mice
title_fullStr Prenatal nutritional intervention reduces autistic-like behavior rates among mthfr-deficient mice
title_full_unstemmed Prenatal nutritional intervention reduces autistic-like behavior rates among mthfr-deficient mice
title_sort prenatal nutritional intervention reduces autistic-like behavior rates among mthfr-deficient mice
publishDate 2019
url https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85068570220&origin=inward
http://cmuir.cmu.ac.th/jspui/handle/6653943832/65844
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