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J Neurosci. 2017 Jul 19;37(29):6851-6868. doi: 10.1523/JNEUROSCI.3516-16.2017. Epub 2017 Jun 19.

Amplification of mGlu5-Endocannabinoid Signaling Rescues Behavioral and Synaptic Deficits in a Mouse Model of Adolescent and Adult Dietary Polyunsaturated Fatty Acid Imbalance.

Manduca A1,2,3, Bara A1,2,3, Larrieu T4,5, Lassalle O1,2,3, Joffre C4,5, Layé S6,5, Manzoni OJ7,2,3.

Author information

1
Institut National de la Santé et de la Recherche Médicale U901, Marseille 13009, France.
2
Institut de Neurobiologie de la Méditerranée, Marseille, France.
3
Université de Aix-Marseille, Unité Mixte de Recherche S901, 13284 Marseille, France.
4
Institut national de la recherche agronomique, Nutrition et Neurobiologie Intégrée, Unité Mixte de Recherche 1286, 33076 Bordeaux, France, and.
5
Université de Bordeaux, 33076, Bordeaux, France.
6
Institut national de la recherche agronomique, Nutrition et Neurobiologie Intégrée, Unité Mixte de Recherche 1286, 33076 Bordeaux, France, and olivier.manzoni@inserm.fr sophie.laye@bordeaux.inra.fr.
7
Institut National de la Santé et de la Recherche Médicale U901, Marseille 13009, France, olivier.manzoni@inserm.fr sophie.laye@bordeaux.inra.fr.

Abstract

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 acids (PUFAs) is a hallmark of poor nutrition and mood disorders. Here, we developed a mouse model of n-3 PUFA 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 LTD in the mPFC and accumbens was abolished in adult n-3-deficient mice. Additionally, mPFC NMDAR-dependent LTP 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 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 PUFA deficiency.SIGNIFICANCE STATEMENT In a mouse model mimicking n-3 PUFA 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 LTD and NMDAR-dependent LTP 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.

KEYWORDS:

LTD; LTP; accumbens; endocannabinoid; mgluR5; prefrontal cortex

PMID:
28630250
DOI:
10.1523/JNEUROSCI.3516-16.2017
[Indexed for MEDLINE]
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