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J Clin Invest. 2017 Dec 1;127(12):4270-4284. doi: 10.1172/JCI94455. Epub 2017 Oct 23.

Deficiency of tumor suppressor NDRG2 leads to attention deficit and hyperactive behavior.

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1, Department of Anesthesiology and Perioperative Medicine.
2, Institute of Neuroscience.
3, Department of Biochemistry and Molecular Biology, and.
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.


Behavior; Mouse models; Neurological disorders; Neuroscience

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