Amplification of mGlu5-endocannabinoid signaling rescues behavioral and synaptic deficits in a mouse model of adolescent and adult dietary polyunsaturated fatty acids imbalance.

Energy-dense, yet nutritionally-poor food is a high-risk factor for mental health disorders. This is of particular concern during adolescence, a period often associated with increased consumption of low nutritional content food and higher prevalence of mental health disorders. Indeed, there is an urgent need to understand the mechanisms linking unhealthy diet and mental disorders. Deficiency in n-3 polyunsaturated fatty acid (PUFAs) is a hallmark of poor nutrition and mood disorders. Here, we developed a mouse model of n-3 PUFAs deficiency lasting from adolescence into adulthood. Starting nutritional deficits in dietary n-3 PUFAs during adolescence decreased n-3 PUFAs in both medial prefrontal cortex (mPFC) and nucleus accumbens, increased anxiety-like behavior and decreased cognitive function in adulthood. Importantly, we discovered that endocannabinoid/mGlu₅-mediated long-term depression in the mPFC and accumbens was abolished in adult n-3-deficient mice. Additionally, mPFC NMDAR-dependent long-term potentiation was also lacking in the n-3-deficient group. Pharmacological enhancement of the mGlu₅/eCB signaling complex, by positive allosteric modulation of mGlu₅ or inhibition of endocannabinoid 2-arachidonylglycerol (2-AG) degradation, fully restored synaptic plasticity and normalized emotional and cognitive behaviors in malnourished adult mice. Our data support a model where nutrition is a key environmental factor influencing the working synaptic range into adulthood, long after the end of the perinatal period. These findings have important implications for the identification of nutritional risk factors for disease and design of new treatments for the behavioral deficits associated with nutritional n-3 PUFAs’ deficiency.SIGNIFICANCE STATEMENTIn a mouse model mimicking n-3 PUFAs dietary deficiency during adolescence and adulthood, we found strong increases in anxiety and anhedonia which lead to decreases in specific cognitive functions in adulthood. We found that endocannabinoid/mGlu₅-mediated long-term depression and NMDAR-dependent long-term potentiation were lacking in adult n-3 deficient mice. Acute positive allosteric modulation of mGlu₅ or inhibition of endocannabinoid degradation normalized behaviors and synaptic functions in n-3 PUFA-deficient adult mice. These findings have important implications for the identification of nutritional risk for disease and the design of new treatments for the behavioral deficits associated with nutritional n-3 PUFAs’ imbalance.

Copyright © 2017 the authors.