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.

Multigenerational and transgenerational effects of paternal exposure to drugs of abuse on behavioral and neural function

“…The Wimmer et al . () study suggests that the hippocampus and hippocampus‐dependent learning may be more susceptible to the effects of paternal cocaine exposure. However, multiple factors related to experimental design may also explain these inconsistencies.…”

“…However, cocaine‐sired C57BL/6J mice did not display deficits in a different form of hippocampus‐dependent learning, the Morris water maze (Killinger et al ., ; Fischer et al ., ). Cocaine‐sired male Sprague Dawley rats did not display deficits in a hippocampus‐independent novel object recognition task (Wimmer et al ., ). The Wimmer et al .…”

“…() and Wimmer et al . (). In addition, effects of paternal cocaine exposure may be species‐ or strain‐specific.…”

“…Cocaine-sired adolescent Long Evans rats (PND35) displayed increased perseverance in a T-maze learning task (Abel et al, 1989). Additionally, in a self-administration model of paternal exposure, cocaine-sired adult male Sprague Dawley rats displayed impaired spatial memory, as assessed by a hippocampusdependent spatial object recognition task (Wimmer et al, 2017). Cocaine-sired CD1 mice displayed attention and spatial working memory deficits, as assessed by a 5-arm maze (He et al, 2006).…”

Ageing and epigenetics: linking neurodevelopmental and neurodegenerative disorders

“…4 Most mutations occur at cytosine-phosphate-guanine sites and are associated with the higher methylation environment in male gametogenesis. 10 These changes were associated with increased histone acetylation near the Dao1 gene which reduces D-serine levels, a co-agonist of the Nmethyl-D-aspartate receptor; increasing D-serine levels reversed the memory deficits. Thus, the exact effects of MECP2 mutations may be nuanced and appear potentially reversible.…”