Brain FNDC5/irisin expression in patients and mouse models of major depression.

Major depressive disorder (MDD) is a major cause of disability in adults. MDD is both a co-morbidity and a risk factor for Alzheimer's disease (AD), and regular physical exercise has been associated with reduced incidence and severity of MDD and AD. Irisin is an exercise-induced myokine derived from proteolytic processing of fibronectin type III domain-containing protein 5 (FNDC5). FNDC5/irisin is reduced in the brains of AD patients and mouse models. However, whether brain FNDC5/irisin expression is altered in depression remains elusive. Here, we investigate changes in fndc5 expression in post-mortem brain tissue from MDD individuals and mouse models of depression. We found decreased fndc5 expression in the MDD prefrontal cortex, both with and without psychotic traits. We further demonstrate that induction of depressive-like behavior in male mice by lipopolysaccharide decreased fndc5 expression in the frontal cortex, but not in the hippocampus. Conversely, chronic corticosterone administration increased fndc5 expression in the frontal cortex, but not in the hippocampus. Social isolation in mice did not result in altered fndc5 expression in either frontal cortex or hippocampus. Finally, fluoxetine, but not other antidepressants, increased fndc5 gene expression in the mouse frontal cortex. Results indicate a region-specific modulation of fndc5 in depressive-like behavior and by antidepressant in mice. Our finding of decreased prefrontal cortex fndc5 expression in MDD individuals differs from results in mice, highlighting the importance of carefully interpreting observations in mice. The reduction in fndc5 mRNA suggests that decreased central FNDC5/irisin could comprise a shared pathological mechanism between MDD and AD. Significance Statement Major depressive disorder (MDD) is a major cause of disability in humans. Physical exercise reduces the incidence and severity of MDD, but molecular mechanisms are elusive. One of the pleiotropic actions of exercise alludes to the increased production and circulation of irisin, a myokine cleaved from fibronectin type III domain-containing protein 5 (FNDC5) that mediates some benefits of exercise in the brain. Here, we observed reduced fndc5 expression in post-mortem samples of dorsolateral prefrontal cortex from patients with MDD. In the mouse frontal cortex, modulation of fndc5 was variable across models of depressive-like behavior. Our findings indicate reduced fndc5 expression in MDD with discordant results in mice and stimulate further research on the roles of brain FNDC5/irisin in MDD.