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A Brain Wrought Without Omega-3

2 February 2011. A diet deficient in omega-3 fatty acids interferes with synaptic function, according to a study published January 30 in Nature Neuroscience. Mice chronically deprived of this essential fatty acid showed abnormalities in neurotransmission and plasticity mediated by endocannabinoid receptors, and they seemed prone to anxiety and depression-like behaviors.

Although not directly related to schizophrenia, the study adds to the evidence suggesting a link between improper ratios of different omega fatty acids and mental health (Parker et al., 2006). Present within synaptic membranes, these polyunsaturated fatty acids constitute building blocks of the nervous system, and their incorporation during brain development and beyond may be compromised in brain disorders like schizophrenia (Berger et al, 2006). Consistent with this line of thinking, a study last year suggested that omega-3 fatty acid supplementation with fish oil could help prevent or delay psychosis in vulnerable teens (see SRF related news story).

Humans need to get omega-3 fatty acids from their diet, mainly from fish and certain nuts and vegetables, but the typical Western diet is notorious for its lack of these and a concomitant rise in omega-6 fatty acids. This imbalance prompted Sophie Layé of University of Bordeaux and Olivier Manzoni of INSERM in France to model omega-3 fatty acid deficiency in mice to better understand the impacts in the brain. To mimic a lifelong omega-3 deficiency, the researchers fed a diet lacking omega-3 fatty acid precursors but rich in the omega-6 ones to pregnant mice and to the resulting offspring. They found that this imbalanced diet did indeed translate into abnormal fatty acid levels in the brains of the offspring: in the whole brain and in the prefrontal cortex (PFC), a region implicated in emotional behavior and depression, researchers measured a substantial decrease in the amount of omega-3 fatty acids but an increase in omega-6 fatty acids when compared to mice receiving a diet with appropriate amounts of omega-3 and omega-6 precursors.

Enter endocannabinoids
First authors Mathieu Lafourcade, Thomas Larrieu, and Susana Mato then looked for synaptic abnormalities in brain slices made from mice receiving the omega-3-deficient diet. They focused on the cannabinoid system because polyunsaturated fatty acids can form endogenous ligands ("endocannabinoids") for cannabinoid receptors located on the axon terminals of glutamate-releasing neurons. There, activation of the receptor (CB1R) decreases the amount of neurotransmitter released.

The researchers looked for a form of endocannabinoid-dependent plasticity that they had previously characterized (Lafourcade et al., 2007). While tetanic (repeated) stimulation of the excitatory inputs onto PFC neurons resulted in long-term depression of synaptic currents in control slices, the same protocol did not diminish the size of currents from omega-3-deficient slices. Similarly, this endocannabinoid-mediated plasticity was not found in the nucleus accumbens, a node in brain circuits potentially involved in mood disorders (see SRF related news story), as well as schizophrenia (see, e.g., Floresco et al., 2009), in the omega-3-deficient mice. Other types of synaptic plasticity remained intact, suggesting that the effect of the diet was specific to endocannabinoid-mediated processes.

Further experiments suggested that this defect in plasticity might result from desensitized CB1Rs not working to their full potential. When researchers exposed control slices to a CB1R agonist, this provoked a robust inhibition of excitatory synaptic potentials—an effect consistent with pre-synaptic CB1R activation turning down neurotransmitter release. However, the same treatment produced a much smaller inhibition in slices from omega-3-deficient mice, indicating that the CB1Rs were not as sensitive. Other experiments argued that this diminished function stemmed from CB1Rs that were functionally uncoupled from their effector G proteins, rather than reduced CB1R expression in the omega-3-deficient group. The CB1Rs may have been desensitized in the first place by increased levels of circulating endocannabinoids, something the researchers found indirect evidence for in the omega-3-deficient mice.

A diet for depression?
The researchers then explored the behavioral consequences of the omega-3-deficient diet in mice. In a forced swim test, the amount of time spent immobile—considered a despair-like behavior—was greater in omega-3-deficient mice than in controls. In both groups, this immobility was reversed by the antidepressant imipramine. In the social realm, the omega-3-deficient mice did not explore a new mouse as much as controls did, though they moved around just as much. In an open-field test, which tracks the explorations of a mouse placed inside a walled arena, the omega-3-deficient group spent less time in the center of the arena and more time along the "safer" walls than did controls—behaviors linked to anxiety. To see whether these behaviors were linked to CB1R function, the researchers injected mice with a CB1R agonist to activate CB1Rs. This tilted the control mice toward anxious behavior—spending significantly more time along the walls and less time in the center of the arena; in contrast, the agonist had no effect on the omega-3-deficient group, consistent with the idea that CB1R function was impaired in these mice.

The study begins to outline in mechanistic detail the effects of an omega fatty acid unbalanced diet, and highlights a potential role for the cannabinoid system in mental health. More research will have to explore the links between omega-3-fatty acids, CB1Rs, the PFC, and emotion regulation, and decide whether any of these players offer therapeutic insights into treating depression or schizophrenia.—Michele Solis.

Reference:
Lafourcade M, Larrieu T, Mato S, Duffaud A, Sepers M, Matias I, De Smedt-Peyrusse V, Labrousse VF, Bretillon L, Matute C, Rodríguez-Puertas R, Layé S, Manzoni OJ. Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions. Nat Neurosci. 2011 Jan 30. Abstract

 
Comments on News and Primary Papers
Primary Papers: Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions.

Comment by:  Leonora LongCynthia Shannon Weickert (SRF Advisor)
Submitted 28 July 2011 Posted 28 July 2011

Omega-3 Fatty Acid Levels and Mental Health: Focus on Endocannabinoids and Schizophrenia
Deficiency in dietary omega-3 fatty acid intake appears to favor higher levels of omega-6 acids, which has implications for metabolites downstream of these two fatty acid precursors, including endogenous cannabinoids. While the excellent recent study in Nature Neuroscience (Lafourcade et al., 2011) did not find that increased omega-6 levels corresponded to altered levels of the two major endocannabinoids, 2-AG and anandamide, it did show that it led to a functional reduction of cannabinoid CB1R efficacy and decoupling of CB1R from its inhibitory G protein signaling. This is extremely interesting, given the evidence for changes in endocannabinoid function in schizophrenia (De Marchi et al., 2003; Eggan et al., 2008; Eggan et al., 2010; Dalton et al.,...  Read more


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