Deficiency of transmembrane AMPA receptor regulatory protein γ-8 leads to attention-deficit hyperactivity disorder-like behavior in mice
Wanjun Bai, 河北医科大学中西医结合研究所中药与中药药理教研室, 教育部神经血管生物学重点实验室, 河北医科大学新药药理毒理重点实验室, 中国医学科学院消化道微生态药理毒理研究室, 河北 石家庄 050017, 中国, Xingguang Luο, Baohua Jin, Kangsheng Zhu, Wenyan Guo, Xiaoque Zhu, Xia Qin, Zuxiao Yang, Jiaojiao Zhao, Si-Ruan Chen, Ri Wang, Jie Hao, Fei Wang, Yun Stone Shi, Dezhi Kong, Wei Zhang, 河北省人民医院药学部, 河北 石家庄 050051, 中国, 北京大学回龙观医院, 北京大学回龙观临床医学院, 北京 100096, 中国, 河北医科大学第四医院, 河北 石家庄 050017, 中国, 南京医科大学附属南京脑科医院精神科, 江苏 南京 210029, 中国, 南京大学药物生物技术国家重点实验室, 模式动物与疾病研究教育部重点实验室, 模式动物研究中心, 江苏 南京 210061, 中国
Abstract
Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder prevalent in school-age children. At present, however, its etiologies and risk factors are unknown. Transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (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 exhibited ADHD-like behaviors, including hyperactivity, impulsivity, anxiety, impaired cognition, and memory deficits. Human single-nucleotide polymorphism (SNP) analysis also revealed strong associations between intronic alleles in <i>CACNG8</i> genes 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-8 deficiency, which has great potential for the development of new therapies.