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.
Department of Pharmacy, Hebei General Hospital, Shijiazhuang, Hebei 050051, China.
Zool Res. 2022 Sep 18;43(5):851-870. doi: 10.24272/j.issn.2095-8137.2022.122.
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 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.
注意缺陷多动障碍（ADHD）是一种在学龄儿童中普遍存在的神经发育障碍。然而，目前其病因和危险因素尚不清楚。跨膜α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体调节蛋白γ-8（TARP γ-8，也称为钙电压门控通道辅助亚基γ-8（CACNG8））是一种辅助 AMPA 受体（AMPAR）亚基。在这里，我们报告了 TARP γ-8 与 ADHD 之间的关联，青少年 TARP γ-8 敲除（KO）小鼠表现出类似 ADHD 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）分析也显示，基因中的内含子等位基因与 ADHD 易感性之间存在强烈关联。此外，突触体蛋白质组分析显示，TARP γ-8 KO 小鼠海马体中的 AMPA 谷氨酸受体复合物功能障碍。蛋白质组分析还显示，TARP γ-8 KO 小鼠前额叶皮层中的多巴胺能和谷氨酸能传递失调。哌醋甲酯（MPH）是一种常用于治疗 ADHD 的药物，它显著挽救了 TARP γ-8 KO 小鼠的主要行为缺陷和异常突触蛋白。值得注意的是，MPH 显著逆转了前额叶皮层中 Grik2 和 Slc6a3 的上调。MPH 还通过上调海马体突触体中的其他 AMPAR 辅助蛋白，显著改善了突触 AMPAR 复合物功能。综上所述，我们的结果表明 TARP γ-8 参与了人类 ADHD 的发生。这项研究提供了一个有用的替代动物模型，具有与 TARP γ-8 缺乏相关的 ADHD 样表型，为开发新的治疗方法提供了巨大的潜力。
