Deficiency of tumor suppressor NDRG2 leads to attention deficit and hyperactive behavior
Yan Li, … , Shengxi Wu, Lize Xiong
Yan Li, … , Shengxi Wu, Lize Xiong
Published December 1, 2017; First published October 23, 2017
Citation Information: J Clin Invest. 2017;127(12):4270-4284. https://doi.org/10.1172/JCI94455.
View: Text | PDF
Categories: Research Article Neuroscience

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

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.

Authors

Yan Li, Anqi Yin, Xin Sun, Ming Zhang, Jianfang Zhang, Ping Wang, Rougang Xie, Wen Li, Ze Fan, Yuanyuan Zhu, Han Wang, Hailong Dong, Shengxi Wu, Lize Xiong

×

Figure 1

Ndrg2–/– mice display ADHD-like symptoms.

Options: View larger image (or click on image) Download as PowerPoint
Ndrg2–/– mice display ADHD-like symptoms. (A–D) The locomotor activity ...
(A–D) The locomotor activity of 2-month-old WT and Ndrg2–/– mice in an open field is presented as the total distance traveled (A), number of lines crossed (B), velocity (C), and locomotion in the center of the field (D). n = 10 KO; n = 9 WT. **P < 0.01, Student’s t test. (E–G) Attention and impulsivity were detected in the WT and Ndrg2–/– mice with a visual 5-CSRTT (E) and are represented by the accuracy percentage (F) and premature response percentage (G), respectively. n = 9 KO; n = 9 WT. *P < 0.05; **P < 0.01, Wilcoxon’s rank sum test. (H–J) The short-term (H) and long-term (I) memory of the WT and Ndrg2–/– mice were examined with the novel object recognition test. (J) Heatmaps show the time spent exploring both familiar and novel objects. The circles represent the objects’ locations. n = 9 KO; n = 9 WT. *P < 0.05; **P < 0.01, Wilcoxon’s rank sum test. Error bars indicate mean ± SEM (A–D). Horizontal bars indicate medians (F–I).