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Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions

Nature Neuroscience volume 14, pages 345–350 (2011)Cite this article

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Abstract

The corollaries of the obesity epidemic that plagues developed societies are malnutrition and resulting biochemical imbalances. Low levels of essential n-3 polyunsaturated fatty acids (n-3 PUFAs) have been linked to neuropsychiatric diseases, but the underlying synaptic alterations are mostly unknown. We found that lifelong n-3 PUFAs dietary insufficiency specifically ablates long-term synaptic depression mediated by endocannabinoids in the prelimbic prefrontal cortex and accumbens. In n-3–deficient mice, presynaptic cannabinoid CB1 receptors (CB1Rs) normally responding to endocannabinoids were uncoupled from their effector Gi/o proteins. Finally, the dietary-induced reduction of CB1R functions in mood-controlling structures was associated with impaired emotional behavior. These findings identify a plausible synaptic substrate for the behavioral alterations caused by the n-3 PUFAs deficiency that is often observed in western diets.

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Figure 1: n-3/n-6 PUFA dietary imbalance alters PUFAs level in mouse brain.
Figure 2: Endocannabinoid-dependent synaptic plasticity is absent in n-3–deficient mice.
Figure 3: Nutritional n-3 deficiency did not alter other forms of synaptic plasticity.
Figure 4: Nutritional n-3 deficiency reduces synaptic CB1R efficiency and CB1R coupling to Gi/o-proteins.
Figure 5: Anxiogenic and prodepressant-like effects of dietary n-3 deficiency.

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Acknowledgements

The authors thank O. Lassalle for helping with illustrations, P. Chavis and M. Darnaudéry for helpful discussions, P. Birac and C. Tridon for taking care of the mice and S. Grégoire for technical help. This work was supported by INSERM (O.J.M.), Institut National de la Recherche Agronomique (S.L.), Région Aquitaine (O.J.M. and S.L.), Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED) and the Spanish Ministry of Health (FIS 070628, ISCIII, C.M.M., R.R.P. and S.M.).

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Author notes

  1. Mathieu Lafourcade, Thomas Larrieu and Susana Mato: These authors contributed equally to this work.

  2. Sophie Layé and Olivier J Manzoni: These authors jointly directed this work.

Authors and Affiliations

  1. INSERM U862, Physiopathology of Synaptic Plasticity Group, Neurocentre Magendie, Bordeaux, Cedex, France

    Mathieu Lafourcade, Marja Sepers, Isabelle Matias & Olivier J Manzoni

  2. INRA UMR 1286, CNRS UMR 5226, Nutrition and Integrative Neurobiology, Bordeaux, Cedex, France

    Mathieu Lafourcade, Thomas Larrieu, Anais Duffaud, Marja Sepers, Isabelle Matias, Veronique De Smedt-Peyrusse, Virginie F Labrousse, Sophie Layé & Olivier J Manzoni

  3. University of Bordeaux, Bordeaux, France

    Thomas Larrieu, Anais Duffaud, Veronique De Smedt-Peyrusse, Virginie F Labrousse & Sophie Layé

  4. Department of Neuroscience, University of the Basque Country, Bizkaia, Spain

    Susana Mato & Carlos Matute

  5. UMR1324 CGSA, INRA, Dijon, France

    Lionel Bretillon

  6. Department of Pharmacology, University of the Basque Country, Bizkaia, Spain

    Rafael Rodríguez-Puertas

  7. INSERM U901, Marseille, France

    Olivier J Manzoni

  8. Université de la Méditerranée UMR S901, France

    Olivier J Manzoni

  9. INMED, Marseille, France

    Olivier J Manzoni

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Contributions

M.L. performed the electrophysiology experiments, conducted the data analyses and contributed to the design of the experiments. T.L and A.D. performed the behavioral experiments, conducted the data analyses and contributed to the design of the experiments. S.M. performed the cannabinoid biochemical experiments, conducted the data analyses and contributed to the design of the experiments. M.S. participated in the electrophysiology experiments. R.R.-P. and C.M. participated in the cannabinoid biochemical experiments. I.M. performed the endocannabinoid measurements and conducted the data analyses. V.D.S. performed the western blot experiments and conducted the data analyses. V.F.L. participated in the behavioral experiments. L.B. performed the lipid biochemistry experiments and conducted the data analyses. S.L. and O.J.M. equally supervised the project and wrote the manuscript.

Corresponding authors

Correspondence to Sophie Layé or Olivier J Manzoni.

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Lafourcade, M., Larrieu, T., Mato, S. et al. Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions. Nat Neurosci 14, 345–350 (2011). https://doi.org/10.1038/nn.2736

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