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Paternal cocaine taking elicits epigenetic remodeling and memory deficits in male progeny

An Erratum to this article was published on 21 March 2017

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.

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Acknowledgements

We thank D Van Nest, J Maurer, K Ige, J Karsch, Z Cross and D Lukasz for their help with the experiments, T Abel for comments and extensive discussions on the manuscript and all members of the Pierce lab for their support. We thank the CHOP Metabolomics Core directed by Dr Itzhak Nissim (http://www.research.chop.edu/cores/metabolomic/). This work was supported by NIDA (T32 DA28874, R01 DA33641, K02 DA18678, K01 DA30445, K01 DA039308, R00 DA033372, R21 MH102679, R21 GM110174, DOD W81XWH-13-1-0426).

Author contributions

MEW, LAB, BAG and RCP designed the experiments. MEW, LAB, LAG, ACA, BF, HS, SHD and YH performed experiments. BF, MEW, LAB, SHD and RCP analyzed the data and prepared the figures. MEW and RCP wrote the paper with edits from all authors.

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Correspondence to R C Pierce.

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Wimmer, M., Briand, L., Fant, B. et al. Paternal cocaine taking elicits epigenetic remodeling and memory deficits in male progeny. Mol Psychiatry 22, 1641–1650 (2017). https://doi.org/10.1038/mp.2017.8

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