期刊
MOLECULAR PSYCHIATRY
卷 22, 期 11, 页码 1641-1650出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/mp.2017.8
关键词
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资金
- NIDA [T32 DA28874, R01 DA33641, K02 DA18678, K01 DA30445, K01 DA039308, R00 DA033372, R21 MH102679, R21 GM110174, DOD W81XWH-13-1-0426]
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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