Deficiency of transmembrane AMPA receptor regulatory protein γ-8 leads to attention-deficit hyperactivity disorder-like behavior in mice  

作　　者：Wan-Jun Bai Xing-Guang Luo Bao-Hua Jin Kang-Sheng Zhu Wen-Yan Guo Xiao-Que Zhu Xia Qin Zu-Xiao Yang Jiao-Jiao Zhao Si-Ruan Chen Ri Wang Jie Hao Fei Wang Yun Stone Shi De-Zhi Kong Wei Zhang 

机构地区：[1]Department of Pharmacology,Institution of Chinese Integrative Medicine,Key Laboratory of Neural and Vascular Biology,Ministry of Education,Key Laboratory of New Drug Pharmacology and Toxicology,Hebei Medical University,Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology,Chinese Academy of Medical Sciences,Shijiazhuang,Hebei 050017,China [2]Department of Pharmacy,Hebei General Hospital,Shijiazhuang,Hebei 050051,China [3]Beijing Huilongguan Hospital,Peking University Huilongguan School of Clinical Medicine,Beijing 100096,China [4]Fourth Hospital of Hebei Medical University,Shijiazhuang,Hebei 050017,China [5]Department of Psychiatry,Affiliated Nanjing Brain Hospital,Nanjing Medical University,Nanjing,Jiangsu 210029,China [6]State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study,Model Animal Research Center,Nanjing University,Nanjing,Jiangsu 210061,China

出　　处：《Zoological Research》2022年第5期851-870,共20页动物学研究（英文）

基　　金：supported by the National Natural Science Foundation of China (81872848, 81803509);National Major Special Project on New Drug Innovation grant(2018ZX09711001-004-003);CAMS Innovation Fund for Medical Sciences (2019-I2M-5-055);Hebei Natural Science Foundation(H2019206038);National Key R&D Program of China(2019YFA0801603);Natural Science Foundation of Jiangsu Province (BE2019707)。

摘　　要：Attention-deficit hyperactivity disorder(ADHD) is a neurodevelopmental disorder prevalent in schoolage children. At present, however, its etiologies and risk factors are unknown. Transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid(AMPA) receptor regulatory protein γ-8(TARP γ-8,also known as calcium voltage-gated channel auxiliary subunit gamma 8(CACNG8)) is an auxiliary AMPA receptor(AMPAR) subunit. Here, we report an association between TARP γ-8 and ADHD,whereby adolescent TARP γ-8 knockout(KO) mice exhibitedADHD-likebehaviors,including hyperactivity, impulsivity, anxiety, impaired cognition,and memory deficits. Human single-nucleotide polymorphism(SNP) analysis also revealed strong associations between intronic alleles in CACNG8genes and ADHD susceptibility. In addition,synaptosomal proteomic analysis revealed dysfunction of the AMPA glutamate receptor complex in the hippocampi of TARP γ-8 KO mice.Proteomic analysis also revealed dysregulation of dopaminergic and glutamatergic transmissions in the prefrontal cortices of TARP γ-8 KO mice.Methylphenidate(MPH), which is commonly used to treat ADHD, significantly rescued the major behavioral deficits and abnormal synaptosomal proteins in TARP γ-8 KO mice. Notably, MPH significantly reversed the up-regulation of Grik2 and Slc6a3 in the prefrontal cortex. MPH also significantly improved synaptic AMPAR complex function by up-regulating other AMPAR auxiliary proteins in hippocampal synaptosomes. Taken together, our results suggest that TARP γ-8 is involved in the development of ADHD in humans.This study provides a useful alternative animal model with ADHD-like phenotypes related to TARP γ-8deficiency, which has great potential for the development of new therapies.

关 键 词：Attention-deficit hyperactivity disorder TARPγ-8 METHYLPHENIDATE PROTEOMICS Phenome-wide association study 

分 类 号：R749.94[医药卫生—神经病学与精神病学]