Deficiency of tumor suppressor NDRG2 leads to attention deficit and hyperactive behavior
Deficiency of tumor suppressor NDRG2 leads to attention deficit and hyperactive behavior
复制标题
肿瘤抑制因子 NDRG2 的缺乏会导致注意力缺陷和多动行为。
DOI：
10.1172/jci94455
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发表时间：
2017-12-01
影响因子：
15.9
通讯作者：
Xiong, Lize
中科院分区：
文献类型：
--
作者：
Li, Yan;Yin, Anqi;Xiong, Lize
注意力缺陷多动障碍（ADHD）是一种常见的儿童精神疾病。虽然兴奋性和抑制性输入的不平衡被认为是导致这种疾病的原因，但这种高度异质性疾病的机制在很大程度上仍然未知。在这里，我们表明，N-myc下游调节基因2（NDRG 2）的缺陷是参与ADHD的发展，在小鼠和人类。Ndrg 2基因敲除小鼠表现出ADHD样症状，其特征为注意力缺陷、多动、冲动和记忆力受损。此外，由于星形胶质细胞谷氨酸清除率降低，Ndrg 2（-/-）小鼠脑间质谷氨酸水平和兴奋性传递显著增加。我们开发了一种NDRG 2肽，可挽救星形胶质细胞谷氨酸清除并减少NDRG 2缺陷星形胶质细胞中的兴奋性谷氨酸传递。此外，NDRG 2肽治疗挽救了NDRG 2（-/-）小鼠中的ADHD样多动症，而常规哌甲酯治疗对这些动物中的多动症没有影响。最后，rs 1998848（NDRG 2中的一种SNP）杂合的儿童患ADHD的风险高于rs 1998848纯合的儿童。我们的研究结果表明，NDRG 2缺陷导致ADHD表型和受损的星形胶质细胞谷氨酸清除，一种不同于公认的ADHD多巴胺缺陷假说的机制，是由此产生的行为异常的基础。
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.