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Endocannabinoids: A healthy diet is good for LTD

Nature Reviews Neuroscience 12, 124-125, (March 2011)


A modern Western diet is rich in fats, but often lacks the essential fatty acids α-linolenic acid and linoleic acid, which are required to synthesize long-chain polyunsaturated fatty acids (PUFAs). A new study shows that a lifetime of α-linolenic acid deficiency causes synaptic alterations in the prefrontal cortex (PFC) and changes emotional behaviour in mice.

PUFAs are required for normal brain function, but how a deficiency in PUFAs affects the brain at the synaptic level is not well understood. Lafourcade et al. investigated this issue in mice exposed to α-linolenic acid (n-3)-rich or n-3-deficient diets from gestation onwards. Mice fed on the n-3-deficient diet throughout life (n-3-deficient mice) had lower total brain levels of several n-3 PUFAs and higher levels of n-6 PUFAs — including in the PFC — compared with mice exposed to an n-3-rich diet (n-3 mice). As endocannabinoids are synthesized from PUFAs, the authors went on to investigate the effect of n-3 PUFA deficiency on endocannabinoid-mediated synaptic plasticity.

Tetanic stimulation induced endocannabinoid-mediated long-term depression (LTD) of excitatory synapses in the PFC and in the nucleus accumbens in brain slices from n-3 mice, but this effect was abolished in n-3-deficient mice. Other forms of synaptic plasticity were unaffected by the diet.

The authors then assessed whether the presynaptic cannabinoid 1 receptor (CB1R), a G-protein coupled receptor, mediated this effect. The two groups of mice had similar CB1R levels in the PFC. However, the inhibitory effect of a CB1R agonist on excitatory postsynaptic currents (EPSCs) was much weaker in brain slices from n-3-deficient mice than from n-3 mice. Moreover, in n-3-deficient mice a cannabinoid agonist had a reduced ability to stimulate coupling of CB1R to its G1/0 effector protein. These findings suggest that n-3 deficiency leads to desensitization of CB1Rs in the PFC.

Although the two groups of mice had similar whole-brain levels of the endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), n-3-deficient mice seemed to have higher endocannabinoid levels at synapses: application of a CB1R antagonist increased baseline EPSC in slices from n-3-deficient animals but not n-3 mice, suggesting that CB1Rs were already activated at baseline in n-3-deficient mice. Higher synaptic endocannabinoid levels might be responsible for the desensitization of CB1Rs in the PFC of n-3-deficient mice.

Exposure to the n-3-deficient diet resulted in increased depressive-like behaviour in a forced swim test, reduced social interaction and increased anxiety. Administration of an cannabinoid agonist had an anxiogenic effect on n-3 mice but not n-3-deficient mice, suggesting that at least some of the behavioural effects were mediated by the endocannabinoid system.

A lack of dietary n-3 PUFAs has been associated with mood disorders in humans, and Lafourcade et al. show that alterations in the endocannabinoid system might underlie this link. Moreover, their data suggest that a lack of essential fatty acids in the diet of pregnant and nursing women may have long-lasting consequences for the child.

Leonie Welberg

- Copyright © 2011 Nature Publishing Group, a division of Macmillan Publishers Limited; used with permission



  1. Lafourcade, M. et al. Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions.

    Nature Neurosci. (30 Jan 2011). doi:10.1038/nn.2736

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