Gain of bipolar disorder-related lncRNA AP1AR-DT in mice induces depressive and anxiety-like behaviors by reducing Negr1-mediated excitatory synaptic transmission

作者：Shufen Li, Hongyu Ni, Yaping Wang, Xiaohui Wu, Jianqiang Bi, Haiyan Ou, Zhongwei Li, Junjiao Ping, Zhongju Wang, Ruchuan Chen, Qiong Yang, Meijun Jiang, Liping Cao, Tingyun Jiang, Siqiang Ren, Cunyou Zhao · 发表于：BMC Medicine · 年份：2024 · DOI：10.1186/s12916-024-03725-0 · 被引用次数：8 · 研究领域：Cancer-related molecular mechanisms research、Genetic Associations and Epidemiology、Epigenetics and DNA Methylation

Abstract Background Bipolar disorder is a complex polygenic disorder that is characterized by recurrent episodes of depression and mania, the heterogeneity of which is likely complicated by epigenetic modifications that remain to be elucidated. Methods We performed transcriptomic analysis of peripheral blood RNA from monozygotic (MZ) twins discordant for bipolar disorder to identify disease-associated differentially expressed long noncoding RNAs (DE-lncRNAs), which were further validated in the PsychENCODE brain RNA-seq dataset. We then performed behavioral tests, electrophysiological assays, chromatin immunoprecipitation, and PCR to investigate the function of DE-lncRNAs in the mouse and cell models. Statistical analyses were performed using GraphPad Prism 9.0 or SPSS. Results We identified a bipolar disorder-associated upregulated long non-coding RNA (lncRNA), AP1AR-DT . We observed that overexpression of AP1AR-DT in the mouse medial prefrontal cortex (mPFC) resulted in a reduction of both the total spine density and the spontaneous excitatory postsynaptic current (sEPSC) frequency of mPFC neurons as well as depressive and anxiety-like behaviors. A combination of the results of brain transcriptome analysis of AP1AR-DT overexpressing mice brains with the known genes associated with bipolar disorder revealed that NEGR1 , which encodes neuronal growth regulator 1, is one of the AP1AR-DT targets and is reduced in vivo upon gain of AP1AR-DT in mice. We further demonstrated that ...