FAM19A5/TAFA5, a novel neurokine, plays a crucial role in depressive-like and spatial memory-related behaviors in mice.

FAM19A5/TAFA5 is a member of the family with sequence similarity 19 with unknown function in emotional and cognitive regulation. Here, we reported that FAM19A5 was highly expressed in the embryonic and postnatal mouse brain, especially in the hippocampus. Behaviorally, genetic deletion of Fam19a5 resulted in increased depressive-like behaviors and impaired hippocampus-dependent spatial memory. These behavioral alterations were associated with the decreased expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and N-methyl-D-aspartic acid receptors, as well as significantly reduced glutamate release and neuronal activity in the hippocampus. Subsequently, these changes led to the decreased density of dendritic spines. In recent years, the roles of chronic stress participating in the development of depression have become increasingly clear, but the mechanism remains to be elucidated. We found that the levels of FAM19A5 in plasma and hippocampus of chronic stress-treated mice were significantly decreased whereas overexpression of human FAM19A5 selectively in the hippocampus could attenuate chronic stress-induced depressive-like behaviors. Taken together, our results revealed for the first time that FAM19A5 plays a key role in the regulation of depression and spatial cognition in the hippocampus. Furthermore, our study provided a new mechanism for chronic stress-induced depression, and also provided a potential biomarker for the diagnosis and a new strategy for the treatment of depression.