Abstract
Depression is a mental disorder affecting more than 300 million people in the world. Abnormalities in white matter are associated with the development of depression. Here, the authors show that mice with oligodendrocyte-specific deletion of Nerve injury-induced protein 2 （Ninj2) exhibit depressive-like behaviors. Loss of Ninj2 in oligodendrocytes inhibits oligodendrocyte development and myelination, and impairs neuronal structure and activities. Ninj2 competitively inhibits TNFα/TNFR1 signaling pathway by directly binding to TNFR1 in oligodendrocytes. Loss of Ninj2 activates TNFα-induced necroptosis, and increases C-C Motif Chemokine Ligand 2 (Ccl2) production, which might mediate the signal transduction from oligodendrocyte to neurons. Inhibition of necroptosis by Nec-1s administration synchronously restores oligodendrocyte development, improves neuronal excitability, and alleviates depressive-like behaviors. This study thus illustrates the role of Ninj2 in the development of depression and myelination, reveals the relationship between oligodendrocytes and neurons, and provides a potential therapeutic target for depression.