机构:[1]Department of Anesthesiology and Perioperative Medicine,Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China[2]Institute of Neuroscience,Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China[3]Department of Biochemistry and Molecular Biology,Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China[4]Department of Pediatrics, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China.[5]General Hospital of Chengdu Military Command, Chengdu, Sichuan, China.[6]Department of Gynecology and Obstetrics, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China.[7]School of Biology and Basic Medical Sciences, Medical College, Soochow University, Suzhou, Jiangsu, China.
Attention-deficit/hyperactivity disorder (ADHD) is a prevalent psychiatric disorder in children. Although an imbalance of excitatory and inhibitory inputs has been proposed as contributing to this disorder, the mechanisms underlying this highly heterogeneous disease remain largely unknown. Here, we show that N-myc downstream-regulated gene 2 (NDRG2) deficiency is involved in the development of ADHD in both mice and humans. Ndrg2-knockout (Ndrg2-/-) mice exhibited ADHD-like symptoms characterized by attention deficits, hyperactivity, impulsivity, and impaired memory. Furthermore, interstitial glutamate levels and excitatory transmission were markedly increased in the brains of Ndrg2-/- mice due to reduced astroglial glutamate clearance. We developed an NDRG2 peptide that rescued astroglial glutamate clearance and reduced excitatory glutamate transmission in NDRG2-deficient astrocytes. Additionally, NDRG2 peptide treatment rescued ADHD-like hyperactivity in the Ndrg2-/- mice, while routine methylphenidate treatment had no effect on hyperactivity in these animals. Finally, children who were heterozygous for rs1998848, a SNP in NDRG2, had a higher risk of ADHD than children who were homozygous for rs1998848. Our results indicate that NDRG2 deficiency leads to ADHD phenotypes and that impaired astroglial glutamate clearance, a mechanism distinct from the well-established dopamine deficit hypothesis for ADHD, underlies the resultant behavioral abnormalities.
基金:
The present study was supported by the
National Natural Science Foundation of China (81420108013
to LX; 81471110, 81671184 to YL), the National Key Technology
Research and Development Program of the Ministry of Science
and Technology of China (2012BAI11B02 to LX) and the National
Basic Research Program of China (2014CB543202 to LX).
语种:
外文
PubmedID:
中科院(CAS)分区:
出版当年[2017]版:
大类|1 区医学
小类|1 区医学:研究与实验
最新[2023]版:
大类|1 区医学
小类|1 区医学:研究与实验
第一作者:
第一作者机构:[1]Department of Anesthesiology and Perioperative Medicine,Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China[2]Institute of Neuroscience,Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China[3]Department of Biochemistry and Molecular Biology,Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China[*1]Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi’an, Shaanxi Province, 710032, China.
共同第一作者:
通讯作者:
通讯机构:[1]Department of Anesthesiology and Perioperative Medicine,Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China[2]Institute of Neuroscience,Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China[3]Department of Biochemistry and Molecular Biology,Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China[*1]Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, 127 Changle West Road, Xi’an, Shaanxi Province, 710032, China.
推荐引用方式(GB/T 7714):
Yan Li,Anqi Yin,Xin Sun,et al.Deficiency of tumor suppressor NDRG2 leads to attention deficit and hyperactive behavior.[J].The Journal of clinical investigation.2017,127(12):4270-4284.doi:10.1172/JCI94455.
APA:
Yan Li,Anqi Yin,Xin Sun,Ming Zhang,Jianfang Zhang...&Lize Xiong.(2017).Deficiency of tumor suppressor NDRG2 leads to attention deficit and hyperactive behavior..The Journal of clinical investigation,127,(12)
MLA:
Yan Li,et al."Deficiency of tumor suppressor NDRG2 leads to attention deficit and hyperactive behavior.".The Journal of clinical investigation 127..12(2017):4270-4284