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 October 23, 2017
Citation Information: J Clin Invest. 2017;127(12):4270-4284. https://doi.org/10.1172/JCI94455.
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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

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Figure 2

Enhanced excitatory transmission in the Ndrg2–/– brain.

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Enhanced excitatory transmission in the Ndrg2–/– brain. (A) Representati...
(A) Representative traces and spectrogram of θ EEG rhythms in WT and Ndrg2–/– mice. (B) Quantitative θ rhythm percentage of the total EEG in the frontal cortex of the WT and Ndrg2–/– mice. n = 6 KO; n = 6 WT. *P < 0.05, Wilcoxon’s rank sum test. (C–E) Measurements of interstitial glutamate and dopamine concentrations in the mPFC (C), hippocampus (Hip.) (D), or striatum (E) of WT and Ndrg2–/– mice. n = 6 per group. **P < 0.01, Student’s t test. (F) Representative sEPSC recordings in the WT and Ndrg2–/– hippocampal CA1 pyramidal neurons (upper trace). Amplitudes and frequencies of the sEPSCs (lower histogram, left and right, respectively) were quantified. n = 12 per group. **P < 0.01, Student’s t test. Error bars indicate mean ± SEM.