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Reduction of DNMT3a and RORA in the nucleus accumbens plays a causal role in post-traumatic stress disorder-like behavior: reversal by combinatorial epigenetic therapy

Abstract

Post-traumatic stress disorder (PTSD) is an incapacitating trauma-related disorder, with no reliable therapy. Although PTSD has been associated with epigenetic alterations in peripheral white blood cells, it is unknown where such changes occur in the brain, and whether they play a causal role in PTSD. Using an animal PTSD model, we show distinct DNA methylation profiles of PTSD susceptibility in the nucleus accumbens (NAc). Data analysis revealed overall hypomethylation of different genomic CG sites in susceptible animals. This was correlated with the reduction in expression levels of the DNA methyltransferase, DNMT3a. Since epigenetic changes in diseases involve different gene pathways, rather than single candidate genes, we next searched for pathways that may be involved in PTSD. Analysis of differentially methylated sites identified enrichment in the RAR activation and LXR/RXR activation pathways that regulate Retinoic Acid Receptor (RAR) Related Orphan Receptor A (RORA) activation. Intra-NAc injection of a lentiviral vector expressing either RORA or DNMT3a reversed PTSD-like behaviors while knockdown of RORA and DNMT3a increased PTSD-like behaviors. To translate our results into a potential pharmacological therapeutic strategy, we tested the effect of systemic treatment with the global methyl donor S-adenosyl methionine (SAM), for supplementing DNA methylation, or retinoic acid, for activating RORA downstream pathways. We found that combined treatment with the methyl donor SAM and retinoic acid reversed PTSD-like behaviors. Thus, our data point to a novel approach to the treatment of PTSD, which is potentially translatable to humans.

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Fig. 1: Behavioral response in the PTSD model.
Fig. 2: Susceptibility and resilient DNA methylation profile.
Fig. 3: Effect of intra-NAc RORA and DNMT3a overexpression and knockdown on PTSD-like behavior.
Fig. 4: Effect of SAM and retinoic acid treatment on PTSD-like behaviors.

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Acknowledgements

This study was funded by a grant from the Canadian Institute of Health Research MOP-42411 to MS and the Israel Academy of Sciences 1612/14 to GY. SAM used in this study was a kind gift of Life Science Laboratories LLC Lakewood NJ USA. We thank Dr. Tamar Sadan for the critical editing of the manuscript. This work was performed in partial fulfillment of the requirements for a Ph.D. degree to GW, The Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University.

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Correspondence to Moshe Szyf or Gal Yadid.

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The authors have applied for patents for discoveries reported here and licensed the patent to Neuroepitherapeutics Inc.

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Warhaftig, G., Zifman, N., Sokolik, C.M. et al. Reduction of DNMT3a and RORA in the nucleus accumbens plays a causal role in post-traumatic stress disorder-like behavior: reversal by combinatorial epigenetic therapy. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01178-y

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