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 CACNG8 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.
注意力缺陷多动障碍（ADHD）是一种神经发育障碍性疾病，频发于学龄期儿童，但其发病机制和诱因至今尚不明确。TARP γ-8，也称为钙电压门控通道辅助亚基γ8（CACNG8），是谷氨酸能AMPA受体（AMPAR）的辅助调节蛋白。该研究揭示了TARP γ-8与ADHD之间的关联性，即TARP γ-8基因敲除（KO）的青春期小鼠表现出ADHD样的行为，包括多动、冲动、焦虑、认知障碍和记忆缺陷；人类单核苷酸多态性 (SNP) 分析也同样表明，CACNG8 基因中的内含子等位基因与 ADHD 的易感性密切相关。此外，突触体蛋白质组学分析揭示了TARP γ-8 KO小鼠的海马组织中存在AMPAR复合物功能紊乱、前额叶皮层中存在多巴胺能和谷氨酸能突触传递调节异常的现象。临床上治疗ADHD的常用药物哌醋甲酯能显著改善TARP γ-8 KO小鼠的主要行为缺陷，并逆转异常表达的突触体蛋白。哌醋甲酯不但显著下调TARP γ-8 KO小鼠前额叶皮层中过度表达的Grik2 和 Slc6a3 蛋白；还通过上调海马突触体中AMPAR的其他辅助蛋白，显著改善突触 AMPAR复合物的功能。总之，该文发现TARP γ-8 参与了人类ADHD的发生发展，TARP γ-8 KO小鼠可作为研究ADHD的候选动物模型，并为ADHD的治疗提供了新的思路。.
Keywords: Attention-deficit hyperactivity disorder; Methylphenidate; Phenome-wide association study; Proteomics; TARP γ-8.