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

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


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.

Keywords: Behavior; Mouse models; Neurological disorders; Neuroscience.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Astrocytes / metabolism*
  • Attention Deficit Disorder with Hyperactivity / drug therapy
  • Attention Deficit Disorder with Hyperactivity / genetics*
  • Attention Deficit Disorder with Hyperactivity / metabolism*
  • Attention Deficit Disorder with Hyperactivity / pathology
  • Behavior, Animal*
  • Dopamine / genetics
  • Dopamine / metabolism
  • Glutamic Acid / genetics
  • Glutamic Acid / metabolism
  • Humans
  • Memory Disorders / drug therapy
  • Memory Disorders / genetics
  • Memory Disorders / metabolism
  • Memory Disorders / physiopathology
  • Methylphenidate / pharmacology
  • Mice
  • Mice, Knockout
  • Polymorphism, Single Nucleotide
  • Proteins / genetics*
  • Proteins / metabolism
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism


  • Adaptor Proteins, Signal Transducing
  • NDRG2 protein, human
  • Ndr2 protein, mouse
  • Proteins
  • Tumor Suppressor Proteins
  • Methylphenidate
  • Glutamic Acid
  • Dopamine