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      A paternal methyl donor-rich diet altered cognitive and neural functions in offspring mice

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          Abstract

          Dietary intake of methyl donors, such as folic acid and methionine, shows considerable intra-individual variation in human populations. While it is recognized that maternal departures from the optimum of dietary methyl donor intake can increase the risk for mental health issues and neurological disorders in offspring, it has not been explored whether paternal dietary methyl donor intake influences behavioral and cognitive functions in the next generation. Here, we report that elevated paternal dietary methyl donor intake in a mouse model, transiently applied prior to mating, resulted in offspring animals (methyl donor-rich diet (MD) F1 mice) with deficits in hippocampus-dependent learning and memory, impaired hippocampal synaptic plasticity and reduced hippocampal theta oscillations. Gene expression analyses revealed altered expression of the methionine adenosyltransferase Mat2a and BK channel subunit Kcnmb2, which was associated with changes in Kcnmb2 promoter methylation in MD F1 mice. Hippocampal overexpression of Kcnmb2 in MD F1 mice ameliorated altered spatial learning and memory, supporting a role of this BK channel subunit in the MD F1 behavioral phenotype. Behavioral and gene expression changes did not extend into the F2 offspring generation. Together, our data indicate that paternal dietary factors influence cognitive and neural functions in the offspring generation.

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          Most cited references 47

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          Synaptic plasticity and memory: an evaluation of the hypothesis.

          Changing the strength of connections between neurons is widely assumed to be the mechanism by which memory traces are encoded and stored in the central nervous system. In its most general form, the synaptic plasticity and memory hypothesis states that "activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation and is both necessary and sufficient for the information storage underlying the type of memory mediated by the brain area in which that plasticity is observed." We outline a set of criteria by which this hypothesis can be judged and describe a range of experimental strategies used to investigate it. We review both classical and newly discovered properties of synaptic plasticity and stress the importance of the neural architecture and synaptic learning rules of the network in which it is embedded. The greater part of the article focuses on types of memory mediated by the hippocampus, amygdala, and cortex. We conclude that a wealth of data supports the notion that synaptic plasticity is necessary for learning and memory, but that little data currently supports the notion of sufficiency.
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            Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription.

            CpG methylation in vertebrates correlates with alterations in chromatin structure and gene silencing. Differences in DNA-methylation status are associated with imprinting phenomena and carcinogenesis. In Xenopus laevis oocytes, DNA methylation dominantly silences transcription through the assembly of a repressive nucleosomal array. Methylated DNA assembled into chromatin binds the transcriptional repressor MeCP2 which cofractionates with Sin3 and histone deacetylase. Silencing conferred by MeCP2 and methylated DNA can be relieved by inhibition of histone deacetylase, facilitating the remodelling of chromatin and transcriptional activation. These results establish a direct causal relationship between DNA methylation-dependent transcriptional silencing and the modification of chromatin.
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              Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder.

               Q. Chen,  M. Yan,  Z. Cao (2016)
              Increasing evidence indicates that metabolic disorders in offspring can result from the father's diet, but the mechanism remains unclear. In a paternal mouse model given a high-fat diet (HFD), we showed that a subset of sperm transfer RNA-derived small RNAs (tsRNAs), mainly from 5' transfer RNA halves and ranging in size from 30 to 34 nucleotides, exhibited changes in expression profiles and RNA modifications. Injection of sperm tsRNA fractions from HFD males into normal zygotes generated metabolic disorders in the F1 offspring and altered gene expression of metabolic pathways in early embryos and islets of F1 offspring, which was unrelated to DNA methylation at CpG-enriched regions. Hence, sperm tsRNAs represent a paternal epigenetic factor that may mediate intergenerational inheritance of diet-induced metabolic disorders.
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                Author and article information

                Journal
                Mol Psychiatry
                Mol. Psychiatry
                Molecular Psychiatry
                Nature Publishing Group
                1359-4184
                1476-5578
                May 2018
                04 April 2017
                : 23
                : 5
                : 1345-1355
                Affiliations
                [1 ]Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE) , Bonn, Germany
                [2 ]Department of Neuropsychopharmacology, Federal Institute for Drugs and Medical Devices (BfArM) , Bonn, Germany
                [3 ]Department of Physiology, Medical College of Qingdao University , Qingdao, Shandong, China
                [4 ]Department of Psychiatry and Psychotherapy, University of Cologne, Faculty of Medicine , Cologne, Germany
                [5 ]German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health , Neuherberg, Germany
                [6 ]Friedrich-Baur-Institut, Department of Neurology, Ludwig-Maximilians-Universität München , Munich, Germany
                [7 ]Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health , Neuherberg, Germany
                [8 ]Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health , Neuherberg, Germany
                [9 ]Institute of Molecular Psychiatry, Medical Faculty, University of Bonn , Bonn, Germany
                [10 ]Chair of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München , Munich, Germany
                [11 ]Member of German Center for Diabetes Research (DZD) , München-Neuherberg, Germany
                [12 ]Department of Internal Medicine I, University Hospital Carl Gustav Carus, Technical University Dresden , Dresden, Germany
                [13 ]Molecular Nutritional Medicine, Else Kröner-Fresenius Center, Technische Universität München , Freising-Weihenstephan, Germany
                [14 ]German Center for Vertigo and Balance Disorders, University Hospital Munich, Campus Grosshadern , Munich, Germany
                [15 ]DZNE, German Center for Neurodegenerative Diseases , Munich, Germany
                [16 ]Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München , Munich, Germany
                [17 ]Chair of Developmental Genetics, Technische Universität München, c/o Helmholtz Zentrum München, German Research Center for Environmental Health , Neuherberg, Germany
                [18 ]Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München , Freising-Weihenstephan, Germany
                [19 ]Department of Biology, University of Crete, Vassilika Vouton , Heraklio, Greece
                Author notes
                [* ]Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE) , Sigmund-Freud-Str. 27, Bonn 53127, Germany. E-mail: Dan.Ehninger@ 123456dzne.de
                Article
                mp201753
                10.1038/mp.2017.53
                5984088
                28373690
                Copyright © 2018 The Author(s)

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                Categories
                Original Article

                Molecular medicine

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