RESUMEN
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.
Asunto(s)
Cocaína/farmacología , Memoria/efectos de los fármacos , Exposición Paterna/efectos adversos , Animales , Conducta Animal/efectos de los fármacos , Cocaína/efectos adversos , Cognición/efectos de los fármacos , Epigénesis Genética/genética , Epigenómica/métodos , Femenino , Hipocampo/metabolismo , Histonas/metabolismo , Masculino , Trastornos de la Memoria/metabolismo , Plasticidad Neuronal/efectos de los fármacos , Núcleo Accumbens/metabolismo , Herencia Paterna/genética , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Factores SexualesRESUMEN
This corrects the article DOI: 10.1038/mp.2017.8.