Abstract
Despite significant advances in the understanding of the therapeutic activity of antidepressant drugs, treatment-resistant depression is a public health issue prompting research to identify new therapeutic strategies. Evidence strongly suggests that nutrition might exert a significant impact on the onset, the duration and the severity of major depression. Accordingly, preclinical and clinical investigations demonstrated the beneficial effects of omega-3 fatty acids in anxiety and mood disorders. Although the neurobiological substrates of its action remain poorly documented, basic research has shown that omega-3 increases brain-derived neurotrophic factor (BDNF) levels in brain regions associated with depression, as antidepressant drugs do. In contrast, low BDNF levels and hippocampal atrophy were observed in animal models of depression. In this context, the present study compared the effects of long-lasting fish oil-enriched diet, an important source of omega-3 fatty acids, between heterozygous BDNF+/- mice and their wild-type littermates. Our results demonstrated lower activation of Erk in BDNF+/- mice whereas this deficit was rescued by fish oil-enriched diet. In parallel, BDNF+/- mice displayed elevated hippocampal extracellular 5-HT levels in relation with a local decreased serotonin transporter protein level. Fish oil-enriched diet restored normal serotonergic tone by increasing the protein levels of serotonin transporter. At the cellular level, fish oil-enriched diet increased the pool of immature neurons in the dentate gyrus of BDNF+/- mice and the latter observations coincide with its ability to promote anxiolytic- and antidepressant-like response in these mutants. Collectively, our results demonstrate that the beneficial effects of long-term exposure to fish oil-enriched diet in behavioral paradigms known to recapitulate diverse abnormalities related to the depressive state specifically in mice with a partial loss of BDNF. These findings contrast with the mechanism of action of currently available antidepressant drugs for which the full manifestation of their therapeutic activity depends on the enhancement of serotoninergic and BDNF signaling. Further studies are warranted to determine whether fish oil supplementation could be used as an add-on strategy to conventional pharmacological interventions in treatment-resistant patients and relevant animal models.
Highlights
Major depressive disorder (MDD) is an important public health concern worldwide
Using behavioral paradigms assessing anxiolytic/antidepressant-like activities, we examined whether fish oil-enriched diet represents an alternative therapeutic strategy to currently available antidepressant drugs in Brain-Derived Neurotrophic Factor (BDNF)+/− mice
Because initial studies demonstrated that forebrain BDNF mRNA and protein levels in BDNF+/− mice were ≈50% of the wild-type (Ernfors et al, 1994; Korte et al, 1995; Kolbeck et al, 1999), the activation of ErK and Akt in the hippocampus was used in the present study as an indirect marker of changes in BDNF signaling (Schmidt and Duman, 2010; Quesseveur et al, 2013; Lepack et al, 2016)
Summary
The lifetime prevalence of MDD is nowadays 15–20% of the population, and is expected to become the second most prevalent cause of illness-induced disability by 2020 (Lecrubier, 2001) These epidemiological data prompt research to identify the cellular and molecular mechanisms underpinning these mental disorders and to develop innovative treatments with better therapeutic effects than currently available medications. A recent meta-analysis revealed a beneficial overall effect of omega-3 PUFAs in patients under antidepressant drugs treatment (Mocking et al, 2016), suggesting that supplementation with these fatty acids could be used as an “add-on” strategy to reduce treatment resistance, and potentiate treatment response (Peet and Horrobin, 2002; Jazayeri et al, 2008; Gertsik et al, 2012) Consistent with these clinical studies, research in rodents showed that omega-3 PUFAs elicits a robust anxiolytic-like activity in the elevated plus maze (EPM) (Pérez et al, 2013) and an antidepressant-like activity in the forced swim and tail suspension tests (Blondeau et al, 2009; Venna et al, 2009; Moranis et al, 2012; Park et al, 2012; Vines et al, 2012). Omega-3 PUFAs were shown to improve anxiety-like and depressive-like phenotypes in various animal models of depression (Pérez et al, 2013; Pudell et al, 2014; Tang et al, 2015; Wu et al, 2016)
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