title: A paternal methyl donor-rich diet altered cognitive and neural functions in offspring mice.
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.
authors.affiliation: Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: D P
authors.initials: DP
authors.lastname: Ryan
authors.affiliation: Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: K S
authors.initials: KS
authors.lastname: Henzel
authors.affiliation: Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: B L
authors.initials: BL
authors.lastname: Pearson
authors.affiliation: Department of Neuropsychopharmacology, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany.
authors.forename: M E
authors.initials: ME
authors.lastname: Siwek
authors.affiliation: Department of Neuropsychopharmacology, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Papazoglou
authors.affiliation: Department of Physiology, Medical College of Qingdao University, Qingdao, Shandong, China.
authors.forename: L
authors.initials: L
authors.lastname: Guo
authors.affiliation: Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Paesler
authors.affiliation: Department of Physiology, Medical College of Qingdao University, Qingdao, Shandong, China.
authors.forename: M
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Cologne, Faculty of Medicine, Cologne, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Müller
authors.affiliation: Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Xie
authors.affiliation: Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schröder
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Friedrich-Baur-Institut, Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Becker
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Garrett
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: S M
authors.initials: SM
authors.lastname: Hölter
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Institute of Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Neff
authors.affiliation: Institute of Molecular Psychiatry, Medical Faculty, University of Bonn, Bonn, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Rácz
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Chair of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany.|Member of German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Rathkolb
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Member of German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: J
authors.identifier: 0000-0002-8035-8904
authors.initials: J
authors.lastname: Rozman
authors.affiliation: Department of Internal Medicine I, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Ehninger
authors.affiliation: Molecular Nutritional Medicine, Else Kröner-Fresenius Center, Technische Universität München, Freising-Weihenstephan, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Klingenspor
authors.affiliation: Friedrich-Baur-Institut, Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany.|German Center for Vertigo and Balance Disorders, University Hospital Munich, Campus Grosshadern, Munich, Germany.|DZNE, German Center for Neurodegenerative Diseases, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Klopstock
authors.affiliation: Chair of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Wolf
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|DZNE, German Center for Neurodegenerative Diseases, Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, Munich, Germany.|Chair of Developmental Genetics, Technische Universität München, c/o Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Wurst
authors.affiliation: Institute of Molecular Psychiatry, Medical Faculty, University of Bonn, Bonn, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Zimmer
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Fuchs
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Gailus-Durner
authors.affiliation: German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.|Member of German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|Chair of Experimental Genetics, Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Hrabě de Angelis
authors.affiliation: Department of Biology, University of Crete, Vassilika Vouton, Heraklio, Greece.
authors.forename: K
authors.initials: K
authors.lastname: Sidiropoulou
authors.affiliation: Department of Neuropsychopharmacology, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Weiergräber
authors.affiliation: Department of Physiology, Medical College of Qingdao University, Qingdao, Shandong, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Molecular and Cellular Cognition Lab, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Ehninger
mesh_terms: D000818:Animals; D003071:Cognition / Q000502:physiology*; D019175:DNA Methylation; D004032:Diet; D019587:Dietary Supplements / Q000009:adverse effects*; D044127:Epigenesis, Genetic; D005220:Fathers; D005492:Folic Acid / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D007858:Learning / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D008715:Methionine / Q000378:metabolism; D008716:Methionine Adenosyltransferase; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000502:physiology; D000072740:Paternal Inheritance / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic
chemical_list: C000609143:Kcnmb2 protein, mouse; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D005492:Folic Acid; D008715:Methionine; D008716:Methionine Adenosyltransferase