Brain FNDC5/Irisin Expression in Patients and Mouse Models of Major Depression

Abstract

Major depressive disorder (MDD) is a major cause of disability in adults. MDD is both a comorbidity 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 <i>fndc5</i> expression in postmortem brain tissue from MDD individuals and mouse models of depression. We found decreased <i>fndc5</i> expression in the MDD prefrontal cortex, both with and without psychotic traits. We further demonstrate that the induction of depressive-like behavior in male mice by lipopolysaccharide decreased <i>fndc5</i> expression in the frontal cortex, but not in the hippocampus. Conversely, chronic corticosterone administration increased <i>fndc5</i> expression in the frontal cortex, but not in the hippocampus. Social isolation in mice did not result in altered <i>fndc5</i> expression in either frontal cortex or hippocampus. Finally, fluoxetine, but not other antidepressants, increased <i>fndc5</i> gene expression in the mouse frontal cortex. Results indicate a region-specific modulation of <i>fndc5</i> in depressive-like behavior and by antidepressant in mice. Our finding of decreased prefrontal cortex <i>fndc5</i> expression in MDD individuals differs from results in mice, highlighting the importance of carefully interpreting observations in mice. The reduction in <i>fndc5</i> mRNA suggests that decreased central FNDC5/irisin could comprise a shared pathologic mechanism between MDD and AD.