title: Paternal cocaine taking elicits epigenetic remodeling and memory deficits in male progeny.
abstract: Paternal environmental perturbations including exposure to drugs of abuse can produce profound effects on the physiology and behavior of offspring via epigenetic modifications. Here we show that adult drug-naive male offspring of cocaine-exposed sires have memory formation deficits and associated reductions in NMDA receptor-mediated hippocampal synaptic plasticity. Reduced levels of the endogenous NMDA receptor co-agonist d-serine were accompanied by increased expression of the d-serine degrading enzyme d-amino acid oxidase (Dao1) in the hippocampus of cocaine-sired male progeny. Increased Dao1 transcription was associated with enrichment of permissive epigenetic marks on histone proteins in the hippocampus of male cocaine-sired progeny, some of which were enhanced near the Dao1 locus. Finally, hippocampal administration of d-serine reversed both the memory formation and synaptic plasticity deficits. Collectively, these results demonstrate that paternal cocaine exposure produces epigenetic remodeling in the hippocampus leading to NMDA receptor-dependent memory formation and synaptic plasticity impairments only in male progeny, which has significant implications for the male descendants of chronic cocaine users.
authors.affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Wimmer
authors.affiliation: Department of Psychology and Neuroscience, College of Liberal Arts, Temple University, Philadelphia, PA, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Briand
authors.affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Fant
authors.affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Guercio
authors.affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Arreola
authors.affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.|Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: H D
authors.initials: HD
authors.lastname: Schmidt
authors.affiliation: Epigenetic Program, Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sidoli
authors.affiliation: Epigenetic Program, Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Han
authors.affiliation: Epigenetic Program, Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Garcia
authors.affiliation: Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Pierce
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003042:Cocaine / Q000009:adverse effects / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000235:genetics; D057890:Epigenomics / Q000379:methods; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D008297:Male; D008568:Memory / Q000187:drug effects*; D008569:Memory Disorders / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects; D009714:Nucleus Accumbens / Q000378:metabolism; D018812:Paternal Exposure / Q000009:adverse effects*; D000072740:Paternal Inheritance / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D012737:Sex Factors
chemical_list: D006657:Histones; D016194:Receptors, N-Methyl-D-Aspartate; D003042:Cocaine