Major depressive disorder is one of the largest medical and social problems worldwide. Accumulating evidence indicates serotonin neurons in the dorsal raphe nucleus (DRN) play a critical role in pathophysiology of depression as well as its treatment. However, it is unclear whether and how chronic antidepressant treatment and stress alter transcriptome profile of the serotonin neurons, which should determine its activity and ultimately behaviors. To this end, we applied the Translating Ribosome Affinity Purification (TRAP) to isolate the mRNA of serotonin neurons selectively. We performed TRAP of the DRN serotonin neurons in naïve, a selective serotonin reuptake inhibitor (SSRI)-treated mice, as well as resilient and susceptible mice after chronic social defeat stress (CSDS). Differential expression analysis identified 49 presumably prodepressive genes whose expression was decreased in chronic SSRI treated mice and increased in CSDS susceptible mice. Among these, we focused on S100a10 which, in the cortex and lateral habenula, play a key role in depression. To investigate a causal relationship between S100a10 decrease in the DRN and antidepressive phenotype, we infected the viral vector which knockdown S100a10 in serotonin neurons. As expected, S100a10 knockdown mice showed significantly shorter immobility time in the tail suspension test without affecting general locomotor activity. These findings shed light on the molecular mechanism of depression in serotonin neurons and suggest new approaches for the development of antidepressants.