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

Xingyun Xu; Hang Zhou; Hainan Wu; Zhigang Miao; Bo Wan; Haigang Ren; Wei Ge; Guanghui Wang; Xingshun Xu

doi:10.1016/j.celrep.2023.112695

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

Cell Rep. 2023 Jul 25;42(7):112695. doi: 10.1016/j.celrep.2023.112695. Epub 2023 Jul 3.

Authors

Xingyun Xu¹, Hang Zhou², Hainan Wu³, Zhigang Miao³, Bo Wan³, Haigang Ren⁴, Wei Ge⁵, Guanghui Wang⁶, Xingshun Xu⁷

Affiliations

¹ Department of Neurology, the First Affiliated Hospital of Soochow University, Suzhou 215000, China; Institute of Neuroscience, Soochow University, Suzhou 215123, China.
² Institute of Neuroscience, Soochow University, Suzhou 215123, China; PKU-Nanjing Joint Institute of Translational Medicine, Nanjing 211800, China.
³ Institute of Neuroscience, Soochow University, Suzhou 215123, China.
⁴ College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
⁵ Department of Neurology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou 221600, China.
⁶ College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China; Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, Jiangsu 215123, China. Electronic address: wanggh@suda.edu.cn.
⁷ Department of Neurology, the First Affiliated Hospital of Soochow University, Suzhou 215000, China; Institute of Neuroscience, Soochow University, Suzhou 215123, China; Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, Jiangsu 215123, China. Electronic address: xingshunxu@suda.edu.cn.

PMID: 37402169
DOI: 10.1016/j.celrep.2023.112695

Abstract

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.

Keywords: CP: Neuroscience; Sh3rf2; depression; lateral habenula; social preference; ten-eleven translocation 2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Depression / metabolism
Dioxygenases* / metabolism
Habenula* / physiology
Mice
Neurons / metabolism

Substances

Tet2 protein, mouse
DNA-Binding Proteins
Dioxygenases