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. 2017 Nov;22(11):1641-1650.
doi: 10.1038/mp.2017.8. Epub 2017 Feb 21.

Paternal Cocaine Taking Elicits Epigenetic Remodeling and Memory Deficits in Male Progeny

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Paternal Cocaine Taking Elicits Epigenetic Remodeling and Memory Deficits in Male Progeny

M E Wimmer et al. Mol Psychiatry. .
Free PMC article

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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.

Conflict of interest statement

CONFLICT OF INTEREST

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Paternal cocaine self-administration impaired spatial memory formation in male offspring. (a). Sires (F0 generation) were allowed to self-administer cocaine (2 h, daily) for 60 days or received yoked saline infusions. The day following the last self-administration session, males were paired with drug-naive females. Memory formation was assessed in the resulting adult drug-naive first generation (F1) offspring. (b). Animals were exposed to two identical objects and time exploring each item was recorded. After a delay of either 24 h (long-term memory test) or 30 min (short-term test), rats were placed back in the same arena and one of the objects was displaced to a new location. (c). The preference index for all object-based tasks was computed as follows: (time exploring displaced object/total time exploring both objects) × 100. Saline-sired offspring spent equal time exploring both objects during training and show a preference for the displaced object during the long-term memory test. In contrast, progeny of cocaine-exposed sires spent equal time exploring both objects during training and during the 24-h memory test (Interaction between training and siring, F1,17 = 5.178, P =0.0361, n =9–10). (d). Progeny of saline-treated sires showed a preference for the displaced object 30 min after training. Cocaine-sired offspring spent equal time with both objects during the short-term memory test (Interaction between training and siring, F1,16 = 7.457, P = 0.0148, n = 9). (e). A separate cohort of rats was pre-exposed to the training context lacking spatial cues for 5 days prior to training with two identical objects. A novel object was introduced during the object recognition memory test either 24 h or 30 min after training the training session. (f, g). Both groups of animals spent equal time exploring both objects during training and showed a preference for the novel object during the long-term (f, F1,18 = 26.91, P <0.0001, n = 10) and short-term ((g), F1,22 = 19.60, P = 0.0002, n = 11–13) memory tests. For all panels, *P <0.05 comparing train vs test, Bonferroni post hoc test.
Figure 2
Figure 2
Paternal cocaine exposure did not influence spatial memory or object recognition in female offspring. (a) Adult drug-naive female offspring were exposed to two identical objects and time exploring each item was recorded. After a delay of 24 h, animals were placed back in the same arena and one of the objects was displaced to a new location. (b) Both saline- and cocaine-sired progeny show a preference for the displaced object during the long-term memory test (For training, F1,17 = 20.22, P =0.0003, for interaction between training and sire, F1,17 = 0.0444, P = 0.8354, n = 8–11). (c). A separate cohort of rats was pre-exposed to the training context lacking spatial cues for 5 days prior to training with two identical objects. A novel object was introduced during the object recognition memory test 24 h after training the training session. (d) Both groups of female offspring spent equal time exploring both objects during training and showed a preference for the novel object during the long-term memory test (F1,16 = 9.169, P = 0.0080 for training; F1,16 = 0.1791, P = 0.6798 for interaction between training and sire, n = 8–10). *P<0.05 train vs test.
Figure 3
Figure 3
Offspring of cocaine-exposed sires showed impaired long-term potentiation (LTP) and reduced D-serine levels. (a) Theta burst-induced LTP in Schaeffer collateral pathway of the hippocampus was impaired in cocaine-sired offspring compared to controls (F69,1242 = 2.737, P<0.0001, n =7 for saline-sired and n =13 for cocaine-sired). (b) An amino-acid profile screen revealed that total glutamate levels are reduced in the hippocampus of naive adult cocaine-sired offspring compared to controls (F15,180 = 4.012, P <0.0001, n = 6). (c). D-serine levels are diminished in progeny of cocaine-experienced sires (t(10) =2.515, P =0.0307, n =6). TBS, Tris-buffered saline.
Figure 4
Figure 4
Male offspring of cocaine-exposed sires had increased mRNA expression of Dao1 and permissive epigenetic marks were enriched near the Dao1 locus in the hippocampus. (a) D-serine is an endogenous co-agonist that binds to the glycine site of tetrameric N-methyl-D-aspartate receptors (NMDARs). Serine racemase converts L-serine to D-serine in neurons and astrocytes. The enzyme D-amino acid oxidase (DAAO) catalyzes the oxidative deamination of D-serine. We measured the gene expression of the molecules related to NMDAR signaling in the hippocampus of F1 progeny. (b) Gene expression of Grin1, Grin2a, Grin2b and srr was not changed by paternal cocaine exposure (P>0.05, n =7–8). In sharp contrast, the expression of dao1 was increased in the hippocampus of cocaine-sired offspring compared to controls (F4,64 = 4.579, P = 0.0026, n = 7–8, *P <0.05, Bonferroni post hoc test). (c) Globally, 6 epigenetic marks were enriched in the hippocampus of cocaine-sired F1 male offspring (shown in blue above the dotted line; n =6). (d) Chromatin immunoprecipitation against acetylated histone H3 (H3Ac) and single methylated lysine 4 on histone H3 (H3K4me1) revealed enrichment of both marks near the Dao1 gene (H3Ac, F2,18 = 5.326, P = 0.0152; H3K4me1, F2,20 = 6.741, P = 0.0058. *P <0.05 comparing saline- and cocaine-sired fold enrichments, Bonferroni post hoc test; n =5–6). TSS, transcription start site.
Figure 5
Figure 5
D-Serine rescued plasticity and learning deficits related to paternal cocaine self-administration. (a). D-Serine was bath-applied during the entire recording period. Both saline- and cocaine-sired progeny showed theta burst-induced LTP (Time, F69,987 = 21.83, P<0.0001, Interaction between time and sire F69,1242 = 0.3630, P>0.9999; n =7–8). (b). D-Serine or vehicle was microinjected 30 min prior to training on the object location memory task. (c). Vehicle-treated cocaine-sired offspring did not show a preference for the displaced object during short-term memory test compared to controls. All animals treated with D-serine spent more time exploring the displaced object during 30-min memory test (Interaction between training and treatment F3,41 = 4.820, P<0.0058; n =9–14). *P<0.05 comparing train vs test, Bonferroni post hoc test. LTP, long-term potentiation; TBS, Tris-buffered saline.

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