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- Title
Deficiency of tumor suppressor NDRG2 leads to attention deficit and hyperactive behavior.
- Authors
Anqi Yin; Wen Li; Ze Fan; Hailong Dong; Lize Xiong; Rougang Xie; Yan Li; Ming Zhang; Yuanyuan Zhu; Shengxi Wu; Xin Sun; Ping Wang; Jianfang Zhang; Han Wang; Li, Yan; Yin, Anqi; Sun, Xin; Zhang, Ming; Zhang, Jianfang; Wang, Ping
- Abstract
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.
- Subjects
MYC proteins; TUMOR suppressor proteins; ATTENTION-deficit hyperactivity disorder; GLUTAMIC acid; ASTROCYTES; DOPAMINERGIC mechanisms; CHILDREN with attention-deficit hyperactivity disorder; GENETICS; CELL metabolism; PROTEIN metabolism; GLUTAMIC acid metabolism; ANIMAL behavior; ANIMAL experimentation; COMPARATIVE studies; DOPAMINE; GENETIC polymorphisms; RESEARCH methodology; MEDICAL cooperation; MEMORY disorders; METHYLPHENIDATE; MICE; PROTEINS; RESEARCH; EVALUATION research; PHARMACODYNAMICS
- Publication
Journal of Clinical Investigation, 2017, Vol 127, Issue 12, p4270
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI94455