Wimmer M E, Briand L A, Fant B, Guercio L A, Arreola A C, Schmidt H D, Sidoli S, Han Y, Garcia B A, Pierce R C
Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Department of Psychology and Neuroscience, College of Liberal Arts, Temple University, Philadelphia, PA, USA.
Mol Psychiatry. 2017 Nov;22(11):1641-1650. doi: 10.1038/mp.2017.8. Epub 2017 Feb 21.
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.
包括接触滥用药物在内的父源性环境干扰可通过表观遗传修饰对后代的生理和行为产生深远影响。在此我们表明，可卡因暴露雄性亲代的成年未接触过药物的雄性后代存在记忆形成缺陷，且NMDA受体介导的海马突触可塑性相关降低。内源性NMDA受体共激动剂D-丝氨酸水平降低，同时可卡因亲代雄性子代海马中D-丝氨酸降解酶D-氨基酸氧化酶（Dao1）的表达增加。Dao1转录增加与可卡因亲代雄性子代海马中组蛋白上允许性表观遗传标记的富集有关，其中一些在Dao1基因座附近增强。最后，海马内注射D-丝氨酸可逆转记忆形成和突触可塑性缺陷。这些结果共同表明，父源性可卡因暴露在海马中产生表观遗传重塑，仅在雄性子代中导致依赖NMDA受体的记忆形成和突触可塑性受损，这对慢性可卡因使用者的男性后代具有重要意义。
