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Life-long epigenetic programming of cortical architecture by maternal ‘Western’ diet during pregnancy

Molecular Psychiatry volume 25, pages 22–36 (2020)Cite this article

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Abstract

The evolution of human diets led to preferences toward polyunsaturated fatty acid (PUFA) content with ‘Western’ diets enriched in ω-6 PUFAs. Mounting evidence points to ω-6 PUFA excess limiting metabolic and cognitive processes that define longevity in humans. When chosen during pregnancy, ω-6 PUFA-enriched ‘Western’ diets can reprogram maternal bodily metabolism with maternal nutrient supply precipitating the body-wide imprinting of molecular and cellular adaptations at the level of long-range intercellular signaling networks in the unborn fetus. Even though unfavorable neurological outcomes are amongst the most common complications of intrauterine ω-6 PUFA excess, cellular underpinnings of life-long modifications to brain architecture remain unknown. Here, we show that nutritional ω-6 PUFA-derived endocannabinoids desensitize CB1 cannabinoid receptors, thus inducing epigenetic repression of transcriptional regulatory networks controlling neuronal differentiation. We found that cortical neurons lose their positional identity and axonal selectivity when mouse fetuses are exposed to excess ω-6 PUFAs in utero. Conversion of ω-6 PUFAs into endocannabinoids disrupted the temporal precision of signaling at neuronal CB1 cannabinoid receptors, chiefly deregulating Stat3-dependent transcriptional cascades otherwise required to execute neuronal differentiation programs. Global proteomics identified the immunoglobulin family of cell adhesion molecules (IgCAMs) as direct substrates, with DNA methylation and chromatin accessibility profiling uncovering epigenetic reprogramming at >1400 sites in neurons after prolonged cannabinoid exposure. We found anxiety and depression-like behavioral traits to manifest in adult offspring, which is consistent with genetic models of reduced IgCAM expression, to suggest causality for cortical wiring defects. Overall, our data uncover a regulatory mechanism whose disruption by maternal food choices could limit an offspring’s brain function for life.

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Data availability

Proteomic and high-throughput sequencing data were deposited in PRIDE (accession no. PXD016180) and Gene Expression Omnibus (GEO; accession no. GSE140011), respectively.

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Acknowledgements

We thank A. Reinthaler, for her expert laboratory assistance, A. Alpar and T. Hökfelt for discussions, the Biomedical Sequencing Facility at the Center for Molecular Medicine of the Austrian Academy of Sciences for assistance with next-generation sequencing, M. Watanabe (Hokkaido University) for antibodies, and A.F. Pimenta for technical advice with LSAMP cytochemistry. GW Pharmaceuticals (UK) are acknowledged for providing access to an IncuCyte Zoom (Essen Bioscience) live-cell imaging platform. This work was supported by the Swedish Research Council (T.H.); Novo Nordisk Foundation (T.H.); Hjärnfonden (T.H.); European Research Council (SECRET-CELLS, ERC-2015-AdG-695136; T.H.), intramural funds of the Medical University of Vienna (T.H.) and the Wellcome Trust (grant number 094476/Z/10/Z, which funded the purchase of the TripleTOF 5600 mass spectrometer at the BSRC Mass Spectrometry and Proteomics Facility, University of St. Andrews). M.F. is supported by a special research program of the Austrian Science Fund (FWF-F61).

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Author notes

  1. Matthias Farlik

    Present address: Department of Dermatology, Medical University of Vienna, Vienna, Austria

  2. Matthew A. Fuszard

    Present address: Faculty of Medicine, Martin-Luther University, Halle-Wittenberg, Halle, Germany

Authors and Affiliations

  1. Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria

    Valentina Cinquina, Daniela Calvigioni, Erik Keimpema & Tibor Harkany

  2. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

    Matthias Farlik, Florian Halbritter, Victoria Fife-Gernedl & Christoph Bock

  3. School of Chemistry, University of St. Andrews, St. Andrews, United Kingdom

    Sally L. Shirran, Matthew A. Fuszard & Catherine H. Botting

  4. Institut Curie & INSERM U900, Paris, France

    Patrick Poullet

  5. Endocannabinoid Research Group, Institute of Biomolecular Chemistry (ICB), National Research Council (CNR), Pozzuoli, Italy

    Fabiana Piscitelli & Vincenzo Di Marzo

  6. Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary

    Zoltán Máté & Gábor Szabó

  7. Department of Genetic and Behavioral Neuroscience, Gunma University School of Medicine, Maebashi, Japan

    Yuchio Yanagawa

  8. Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria

    Siegfried Kasper

  9. Canada Excellence Research Chair, Institut Universitaire de Cardiologie et de Pneumologie de Québec and Institut sur la Nutrition et les Aliments Fonctionnels, Université Laval, Québec, QC, Canada

    Vincenzo Di Marzo

  10. Department of Psychological & Brain Sciences, Indiana University, Bloomington, Indiana, USA

    Ken Mackie

  11. Program in Developmental Neuroscience, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, NIH, Bethesda, USA

    Chris J. McBain

  12. Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria

    Christoph Bock

  13. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Tibor Harkany

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  1. Valentina Cinquina
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Contributions

TH conceived the project; VC, MF, CB, VDM, CJM, EK and TH designed the experiments; CB, CJB and TH procured funding; VC, DC, MF, VG, MAF, FH, SLS, CHB and FP performed the experiments; VC, DC, MF, FH, PP, FP analyzed the data; ZM, GS and KM developed unique reagents and tools for the project and VC, MF and TH wrote the manuscript with input from all co-authors.

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Correspondence to Tibor Harkany.

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Cinquina, V., Calvigioni, D., Farlik, M. et al. Life-long epigenetic programming of cortical architecture by maternal ‘Western’ diet during pregnancy. Mol Psychiatry 25, 22–36 (2020). https://doi.org/10.1038/s41380-019-0580-4

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