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

Antonia Manduca, Anissa Bara, Thomas Larrieu, Olivier Lassalle, Corinne Joffre, Sophie Layé, Olivier J. Manzoni
J. Neurosci.. 2017-06-19; 37(29): 6851-6868
DOI: 10.1523/JNEUROSCI.3516-16.2017

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1. 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 A(1)(2)(3), Bara A(1)(2)(3), Larrieu T(4)(5), Lassalle O(1)(2)(3), Joffre
C(4)(5), Layé S(6)(5), Manzoni OJ(7)(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
.
(7)Institut National de la Santé et de la Recherche Médicale U901, Marseille
13009, France, .

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.

Copyright © 2017 the authors 0270-6474/17/376852-18$15.00/0.

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

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