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 CB(1) receptors (CB(1)Rs) normally responding to endocannabinoids were uncoupled from their effector G(i/o) proteins.

Finally, the dietary-induced reduction of CB(1)R 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.