Gain of bipolar disorder-related lncRNA AP1AR-DT in mice induces depressive and anxiety-like behaviors by reducing Negr1-mediated excitatory synaptic transmission
Shufen Li,
Hongyu Ni,
Yaping Wang,
Xiaohui Wu,
Jianqiang Bi,
Haiyan Ou,
Zhongwei Li,
Junjiao Ping,
Zhongju Wang,
Renhao Chen,
Qiong Yang,
Meijun Jiang,
Liping Cao,
Tingyun Jiang,
Siqiang Ren,
Cunyou Zhao
Affiliations
Shufen Li
Department of Medical Genetics, Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, and Guangdong Engineering and Technology Research Center for Genetic Testing, School of Basic Medical Sciences, and Guangdong Mental Health Center, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Science), Southern Medical University
Hongyu Ni
Department of Medical Genetics, Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, and Guangdong Engineering and Technology Research Center for Genetic Testing, School of Basic Medical Sciences, and Guangdong Mental Health Center, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Science), Southern Medical University
Yaping Wang
Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, and Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Southern Medical University, Guangzhou
Xiaohui Wu
Department of Medical Genetics, Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, and Guangdong Engineering and Technology Research Center for Genetic Testing, School of Basic Medical Sciences, and Guangdong Mental Health Center, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Science), Southern Medical University
Jianqiang Bi
Shenzhen Kangning Hospital, Shenzhen Mental Health Center
Haiyan Ou
Department of Medical Genetics, Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, and Guangdong Engineering and Technology Research Center for Genetic Testing, School of Basic Medical Sciences, and Guangdong Mental Health Center, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Science), Southern Medical University
Zhongwei Li
Department of Medical Genetics, Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, and Guangdong Engineering and Technology Research Center for Genetic Testing, School of Basic Medical Sciences, and Guangdong Mental Health Center, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Science), Southern Medical University
Junjiao Ping
The Third People’s Hospital of Zhongshan
Zhongju Wang
Department of Medical Genetics, Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, and Guangdong Engineering and Technology Research Center for Genetic Testing, School of Basic Medical Sciences, and Guangdong Mental Health Center, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Science), Southern Medical University
Renhao Chen
Department of Medical Genetics, Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, and Guangdong Engineering and Technology Research Center for Genetic Testing, School of Basic Medical Sciences, and Guangdong Mental Health Center, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Science), Southern Medical University
Qiong Yang
Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital)
Meijun Jiang
Guangdong Mental Health Center, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Science)
Liping Cao
Department of Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital)
Tingyun Jiang
The Third People’s Hospital of Zhongshan
Siqiang Ren
Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong Joint Laboratory for Psychiatric Disorders, Guangdong Province Key Laboratory of Psychiatric Disorders, and Guangdong Basic Research Center of Excellence for Integrated Traditional and Western Medicine for Qingzhi Diseases, Southern Medical University, Guangzhou
Cunyou Zhao
Department of Medical Genetics, Guangdong Technology and Engineering Research Center for Molecular Diagnostics of Human Genetic Diseases, and Guangdong Engineering and Technology Research Center for Genetic Testing, School of Basic Medical Sciences, and Guangdong Mental Health Center, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Science), Southern Medical University
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 overexpression of recombinant Negr1 in the mPFC neurons of AP1AR-DT OE mice ameliorates depressive and anxiety-like behaviors and normalizes the reduced excitatory synaptic transmission induced by the gain of AP1AR-DT. We finally identified that AP1AR-DT reduces NEGR1 expression by competing for the transcriptional activator NRF1 in the overlapping binding site of the NEGR1 promoter region. Conclusions The epigenetic and pathophysiological mechanism linking AP1AR-DT to the modulation of depressive and anxiety-like behaviors and excitatory synaptic function provides etiological implications for bipolar disorder.
