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Hypervulnerability of the adolescent prefrontal cortex to nutritional stress via reelin deficiency

Molecular Psychiatry volume 22, pages 961–971 (2017)Cite this article

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Abstract

Overconsumption of high-fat diets (HFDs) can critically affect synaptic and cognitive functions within telencephalic structures such as the medial prefrontal cortex (mPFC). The underlying mechanisms, however, remain largely unknown. Here we show that adolescence is a sensitive period for the emergence of prefrontal cognitive deficits in response to HFD. We establish that the synaptic modulator reelin (RELN) is a critical mediator of this vulnerability because (1) periadolescent HFD (pHFD) selectively downregulates prefrontal RELN+ cells and (2) augmenting mPFC RELN levels using transgenesis or prefrontal pharmacology prevents the pHFD-induced prefrontal cognitive deficits. We further identify N-methyl-d-aspartate-dependent long-term depression (NMDA-LTD) at prefrontal excitatory synapses as a synaptic signature of this association because pHFD abolishes NMDA-LTD, a function that is restored by RELN overexpression. We believe this study provides the first mechanistic insight into the vulnerability of the adolescent mPFC towards nutritional stress, such as HFDs. Our findings have primary relevance to obese individuals who are at an increased risk of developing neurological cognitive comorbidities, and may extend to multiple neuropsychiatric and neurological disorders in which RELN deficiency is a common feature.

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Acknowledgements

This work was supported by the Swiss National Science Foundation (Grant No. 310030_146217) and the European Union Seventh Framework Program (FP7/2007–2011) (Grant No. 259679) (to UM), by INSERM (to PC), by ETH Zurich (to WL) and by MINECO (Spain, SAF2013-42445R) (to ES). ACR is the recipient of an Australian Research Council Discovery Early Career Research Award (DE140101071). We are grateful to F Mouttet, E Weber, F Müller, S Giovanoli and S Kaufman for assistance in experimentation or genotyping; M Riva and D Ramachandran for helpful discussions; N Jejelava and M Arnold for advice on surgery; and the animal technician team for contribution to animal husbandry. We thank the National Institute of Mental Health's Chemical Synthesis and Drug Supply Program for providing CNQX, NBQX and D-APV.

Author contributions

MAL designed the study, analyzed data, wrote the original manuscript and performed the behavioral, surgical, metabolic and imaging experiments. OL performed and analyzed the electrophysiology experiments. JR and MAL did the western blots. UW contributed to behavior and surgeries. JI developed the LTD protocol. TN, TG and MAL did the immunostainings. LP and ES generated the transgenic mice and contributed to writing. AR, CL and WL contributed to data interpretation and writing. PC and UM designed and supervised the entire study, analyzed data and wrote the manuscript.

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Author notes

  1. P Chavis & U Meyer

    Present address: 13Current address: New York State Psychiatric Institute, Kolb 3rd Floor, 1051 Riverside Drive, Columbia University, New York, NY 10032, USA.,

  2. M A Labouesse: These authors share senior authorship.

Authors and Affiliations

  1. Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland

    M A Labouesse, U Weber-Stadlbauer, W Langhans & U Meyer

  2. Institute of Pharmacology and Toxicology, University of Zurich–Vetsuisse, Zurich, Switzerland

    M A Labouesse, J Richetto, U Weber-Stadlbauer, T Notter & U Meyer

  3. INSERM, INMED UMR S 901, Aix-Marseille Université, Marseille, France

    O Lassalle, J Iafrati & P Chavis

  4. Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland

    T Gschwind

  5. Department of Cell Biology, Physiology and Immunology, University of Barcelona, Barcelona, Spain

    L Pujadas & E Soriano

  6. Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain

    L Pujadas & E Soriano

  7. Vall D́Hebron Institut de Recerca (VHIR), Barcelona, Spain

    L Pujadas & E Soriano

  8. Institució Catalana de Recerca i Estudis Avançats (ICREA Academia), Barcelona, Spain

    E Soriano

  9. School of Health and Biomedical Sciences, RMIT, Melbourne, VIC, Australia

    A C Reichelt

  10. Laboratory of Cell Biophysics, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland

    C Labouesse

  11. Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK

    C Labouesse

  12. Neuroscience Center Zurich (ZNZ), University of Zurich, Zurich, Switzerland

    U Meyer

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  1. M A Labouesse
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Correspondence to M A Labouesse, P Chavis or U Meyer.

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Labouesse, M., Lassalle, O., Richetto, J. et al. Hypervulnerability of the adolescent prefrontal cortex to nutritional stress via reelin deficiency. Mol Psychiatry 22, 961–971 (2017). https://doi.org/10.1038/mp.2016.193

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