Tet2 acts in the lateral habenula to regulate social preference in mice

作者：Xingyun Xu, Xingyun Xu, Hang Zhou, Hainan Wu, Zhigang Miao, Bo Wan, Haigang Ren, Wei Ge, Guanghui Wang, Xingshun Xu, Xingshun Xu · 发表于：Cell Reports · 年份：2023 · DOI：10.1016/j.celrep.2023.112695 · 被引用次数：7 · 研究领域：Neuroendocrine regulation and behavior、Autism Spectrum Disorder Research、Evolutionary Psychology and Human Behavior

The lateral habenula (LHb) has been considered a moderator of social behaviors. However, it remains unknown how LHb regulates social interaction. Here, we show that the hydroxymethylase Tet2 is highly expressed in the LHb. Tet2 conditional knockout (cKO) mice exhibit impaired social preference; however, replenishing Tet2 in the LHb rescues social preference impairment in Tet2 cKO mice. Tet2 cKO alters DNA hydroxymethylation (5hmC) modifications in genes that are related to neuronal functions, as is confirmed by miniature two-photon microscopy data. Further, Tet2 knockdown in the glutamatergic neurons of LHb causes impaired social behaviors, but the inhibition of glutamatergic excitability restores social preference. Mechanistically, we identify that Tet2 deficiency reduces 5hmC modifications on the Sh3rf2 promoter and Sh3rf2 mRNA expression. Interestingly, Sh3rf2 overexpression in the LHb rescues social preference in Tet2 cKO mice. Therefore, Tet2 in the LHb may be a potential therapeutic target for social behavior deficit-related disorders such as autism.