うつ病の分子メカニズム解明へ向けた背側縫線核セロトニン神経特異的な網羅的遺伝子発現変動解析

抄録

Major depressive disorder is one of the largest medical and social problems worldwide. 

Previous studies have shown that the activity of serotonin neurons in the dorsal raphe nucleus (DRN) is increased by chronic administration of a selective serotonin reuptake inhibitor (SSRI) and decreased by chronic social defeat stress (CSDS), a mouse model of depression. These reports have indicated the pivotal role of DRN serotonin neurons in depression, although the underlying mechanism is still unclear. To elucidate the mechanism, we have applied the Translating Ribosome Affinity Purification (TRAP) technique to isolate the mRNA of the DRN serotonin neurons. First, we tried to confirm that TRAP can enrich the serotonin-neuron-specific mRNA and deplete the mRNA of other cell types. Microarray analysis revealed that marker genes of serotonin neurons such as Tph2, Ddc, and Slc6a4 were enriched in immunoprecipitated (IP) samples compared to input, whereas glial marker genes such as Mbp and Gfap were depleted in IP sample. Then we performed TRAP of the DRN serotonin neurons from naïve, SSRI-treated mice, as well as resilient and susceptible mice after CSDS. Differential expression analysis identified 297 genes whose expression was increased by chronic SSRI treatment and decreased by CSDS, and 217 genes was increased by CSDS and decreased by SSRI. Identification of the causal link between the differentially expressed genes and the behavioral changes will help not only to clarify the pathophysiology of depression but also to provide therapeutic targets for drug discovery.