Deficiency of tumor suppressor NDRG2 leads to attention deficit and hyperactive behavior
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
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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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 6

SNP rs1998848 in NDRG2 exon 2 is associated with susceptibility to ADHD and suppression of NDRG2 expression.

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SNP rs1998848 in NDRG2 exon 2 is associated with susceptibility to ADHD ...
(A) Fourteen polymorphic SNPs in a 10-kb region containing the NDRG2 gene. The rs1998848 SNP in exon 2 (star) is the only SNP associated with ADHD susceptibility. The numbers indicate the exon sequence. The open reading frame is located in exon 3. (B) The NDRG2 promoter, exon 1, and exon 2 with the major allele C (pGL3-C) or minor allele T (pGL3-T) of rs1998848 were inserted upstream of the luciferase reporter gene. The pGL3-basic vector (pGL3) was used as a negative control. (C) The relative luciferase activity (firefly luciferase/Renilla luciferase) of pGL3-C, pGL3-T, or pGL3 was analyzed in HEK293 cells. Luciferase activity experiments were performed in triplicate, and data were obtained from 3 independent measurements. *P < 0.05; **P < 0.01, 1-way ANOVA with Tukey-Kramer post hoc test. Error bars indicate mean ± SEM. (D) Relative levels of NDRG2 mRNA in the peripheral blood cells of the heterozygous (CT) patients (5 cases), homozygous (CC) patients (5 cases), and homozygous controls (5 cases). The values were normalized to β-actin, and control 1 was designated 1. Data were obtained from 3 independent measurements, and each experiment was performed in quadruplicate. **P < 0.01, 1-way ANOVA with the Tukey-Kramer post hoc test. Error bars indicate mean ± SEM.