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Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions

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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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.

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Correspondence to Sophie Layé or Olivier J Manzoni.

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The authors declare no competing financial interests.

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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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