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 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 expression in postmortem brain tissue from MDD individuals and mouse models of depression. We found decreased 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 expression in the frontal cortex, but not in the hippocampus. Conversely, chronic corticosterone administration increased expression in the frontal cortex, but not in the hippocampus. Social isolation in mice did not result in altered expression in either frontal cortex or hippocampus. Finally, fluoxetine, but not other antidepressants, increased gene expression in the mouse frontal cortex. Results indicate a region-specific modulation of in depressive-like behavior and by antidepressant in mice. Our finding of decreased prefrontal cortex expression in MDD individuals differs from results in mice, highlighting the importance of carefully interpreting observations in mice. The reduction in mRNA suggests that decreased central FNDC5/irisin could comprise a shared pathologic mechanism between MDD and AD.