title: Correcting miR92a-vGAT-Mediated GABAergic Dysfunctions Rescues Human Tau-Induced Anxiety in Mice.
abstract: Patients with Alzheimer's disease (AD) commonly show anxiety behaviors, but the molecular mechanisms are not clear and no efficient intervention exists. Here, we found that overexpression of human wild-type, full-length tau (termed htau) in hippocampus significantly decreased the extracellular γ-aminobutyric acid (GABA) level with inhibition of γ oscillation and the evoked inhibitory postsynaptic potential (eIPSP). With tau accumulation, the mice show age-dependent anxiety behaviors. Among the factors responsible for GABA synthesis, release, uptake, and transport, we found that accumulation of htau selectively suppressed expression of the intracellular vesicular GABA transporter (vGAT). Tau accumulation increased miR92a, which targeted vGAT mRNA 3' UTR and inhibited vGAT translation. Importantly, we found that upregulating GABA tones by intraperitoneal injection of midazolam (a GABA agonist), ChR2-mediated photostimulating and overexpressing vGAT, or blocking miR92a by using specific antagomir or inhibitor efficiently rescued the htau-induced GABAergic dysfunctions with attenuation of anxiety. Finally, we also demonstrated that vGAT level decreased while the miR92a increased in the AD brains. These findings demonstrate that the AD-like tau accumulation induces anxiety through disrupting miR92a-vGAT-GABA signaling, which reveals molecular mechanisms underlying the anxiety behavior in AD patients and potentially leads to the development of new therapeutics for tauopathies.
authors.affiliation: Department of Pathophysiology, School of Basic Medicine and Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, School of Basic Medicine and Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Key Laboratory for Molecular Diagnosis of Hubei Province, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Tan
authors.affiliation: Department of Pathophysiology, School of Basic Medicine and Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Physiology Department, Henan Provincial Key Laboratory for Brain Research, Xinxiang Medical University, Xinxiang 453000, China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Physiology Department, Henan Provincial Key Laboratory for Brain Research, Xinxiang Medical University, Xinxiang 453000, China.
authors.forename: Chengbiao
authors.initials: C
authors.lastname: Lu
authors.affiliation: State Key Laboratory for Magnet Resonance and Atom and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academia of Science, Wuhan 430071, China.
authors.forename: Rongxiang
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Pathophysiology, School of Basic Medicine and Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Shujuan
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Pathophysiology, School of Basic Medicine and Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Pathophysiology, School of Basic Medicine and Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Yanchao
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pathophysiology, School of Basic Medicine and Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Yaling
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Department of Pathophysiology, School of Basic Medicine and Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Xinghua
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pathophysiology, School of Basic Medicine and Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Enjie
authors.initials: E
authors.lastname: Liu
authors.affiliation: Department of Pathophysiology, School of Basic Medicine and Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pathophysiology, School of Basic Medicine and Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Pathophysiology, School of Basic Medicine and Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Xu
authors.affiliation: State Key Laboratory for Magnet Resonance and Atom and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academia of Science, Wuhan 430071, China.
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Xu
authors.affiliation: State Key Laboratory for Magnet Resonance and Atom and Molecular Physics, Wuhan Institute of Physics and Mathematics, Chinese Academia of Science, Wuhan 430071, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, School of Basic Medicine and Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China. Electronic address: liugp111@mails.tjmu.edu.cn.
authors.forename: Gong-Ping
authors.initials: GP
authors.lastname: Liu
authors.affiliation: Department of Pathophysiology, School of Basic Medicine and Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China. Electronic address: wangjz@mail.hust.edu.cn.
authors.forename: Jian-Zhi
authors.initials: JZ
authors.lastname: Wang
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics; D000818:Animals; D001007:Anxiety / Q000235:genetics* / Q000378:metabolism*; D016000:Cluster Analysis; D004195:Disease Models, Animal; D050485:GABA Plasma Membrane Transport Proteins / Q000235:genetics*; D059330:GABAergic Neurons / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D034622:RNA Interference; D024801:Tauopathies / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism
chemical_list: D050485:GABA Plasma Membrane Transport Proteins; D035683:MicroRNAs; C541873:Mirn92 microRNA, mouse; D016875:tau Proteins
keywords: Alzheimer’s disease; GABA; anxiety; hippocampus; miR92a; neurodegeneration; tau; tauopathies; vGAT; γ oscillations