Prenatal Nutritional Intervention Reduces Autistic-Like Behavior Rates Among Mthfr-Deficient Mice
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 e...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-05-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2019.00383/full |
| _version_ | 1818251521388707840 |
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| author | Ayelet Orenbuch Keren Fortis Siraphat Taesuwan Siraphat Taesuwan Raz Yaffe Marie A. Caudill Hava M. Golan Hava M. Golan |
| author_facet | Ayelet Orenbuch Keren Fortis Siraphat Taesuwan Siraphat Taesuwan Raz Yaffe Marie A. Caudill Hava M. Golan Hava M. Golan |
| author_sort | Ayelet Orenbuch |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T16:09:36Z |
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| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-12T16:09:36Z |
| publishDate | 2019-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-03431facc24c46c1a9f5618b3f5ef93e2022-12-22T00:19:13ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2019-05-011310.3389/fnins.2019.00383446125Prenatal Nutritional Intervention Reduces Autistic-Like Behavior Rates Among Mthfr-Deficient MiceAyelet Orenbuch0Keren Fortis1Siraphat Taesuwan2Siraphat Taesuwan3Raz Yaffe4Marie A. Caudill5Hava M. Golan6Hava M. Golan7Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beersheba, IsraelDepartment of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beersheba, IsraelDivision of Nutritional Sciences, Cornell University, Ithaca, NY, United StatesDivision of Food Science and Technology, Faculty of Agro-Industry, Chiang Mai University, Chiang Mai, ThailandDepartment of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beersheba, IsraelDivision of Nutritional Sciences, Cornell University, Ithaca, NY, United StatesDepartment of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beersheba, IsraelZlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beersheba, IsraelThe 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.https://www.frontiersin.org/article/10.3389/fnins.2019.00383/fullautismone-carbon metabolismcholineGABAglutamate receptorsH3 |
| spellingShingle | Ayelet Orenbuch Keren Fortis Siraphat Taesuwan Siraphat Taesuwan Raz Yaffe Marie A. Caudill Hava M. Golan Hava M. Golan Prenatal Nutritional Intervention Reduces Autistic-Like Behavior Rates Among Mthfr-Deficient Mice Frontiers in Neuroscience autism one-carbon metabolism choline GABA glutamate receptors H3 |
| title | 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_short | 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 |
| topic | autism one-carbon metabolism choline GABA glutamate receptors H3 |
| url | https://www.frontiersin.org/article/10.3389/fnins.2019.00383/full |
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