Abstract
Abnormal neuronal morphological features, such as dendrite branching, axonal branching, and spine density, is thought to contribute to the symptoms of depression and anxiety. However, the role and molecular mechanisms of aberrant neuronal morphology in the regulation of mood disorders remain poorly characterized. Here, we show that Neuritin, an activity-dependent protein, regulates the axonal morphology of serotonin neurons. Male neuritin knockout mice harbored impaired axonal branches of serotonin neurons in the medial prefrontal cortex and basolateral region of the amygdala (BLA), and male neuritin knockout mice exhibited depressive and anxiety-like behaviors. We also observed that the expression of Neuritin was decreased by unpredictable chronic stress (UCS) in the male mouse brain and that decreased expression of neuritin was associated with reduced axonal branching of serotonin neurons in the brain and with depressive and anxiety behaviors in mice. Furthermore, the stress-mediated impairments in axonal branching and depressive behaviors were reversed by the overexpression of Neuritin in the BLA. The ability of neuritin to increase axonal branching in serotonin neurons involves FGF signaling, and neuritin contributes to FGF-2-mediated axonal branching regulation in vitro. Finally, the oral administration of an FGF inhibitor reduced the axonal branching of serotonin neurons in the brain and caused depressive and anxiety behaviors in male mice. Our results support the involvement of neuritin in models of stress-induced depression and suggest that neuronal morphological plasticity may play a role in controlling animal behavior.
Significance statement Axonal atrophy of serotonin neurons is one of the representative neuroanatomical features of depression. We found that the secreted/membrane-anchored neurotrophic factor Neuritin regulated axonal branch formation, which is involved in the development of depression and anxiety. In addition, Neuritin and the secreted signaling protein fibroblast growth factor 2 (FGF-2) cooperate to promote axonal branching in serotonin neurons. Furthermore, the inhibition of FGF signaling promoted axonal branching impairments and depressive behavior in mice. Taken together, these findings suggest that Neuritin regulates axonal branching in serotonin neurons and that the loss of neuritin is related to the development of depression. FGF signaling is involved in the neuritin-mediated axonal branching of serotonin neurons.
Footnotes
The authors declare that they have no conflicts of interest.
This work was supported in part by JSPS KAKENHI Grants-in-Aid for Scientific Research 18H02536 and 22K07949 (K.Y.), 17K07086 and 22K06493 (T.S.). We thank Drs. Akiyo Natsubori and Ran Inoue for their critical instructions concerning virus injection, Dr. Hiroshi Sakuma for the helpful discussion, and Ms. Fumie Masuda and Ms. Nobuko Ogawa for their support in the quantification and genotyping methods.
