Chronic Administration of the N-Methyl-D-Aspartate Receptor Antagonist Ketamine Improves Rett Syndrome Phenotype

Biol Psychiatry. 2016 May 1;79(9):755-764. doi: 10.1016/j.biopsych.2015.08.018. Epub 2015 Aug 24.


Background: Rett syndrome (RTT) is a neurological disorder caused by mutation of the X-linked MECP2 gene, which results in the progressive disruption of excitatory and inhibitory neuronal circuits. To date, there is no effective treatment available for the disorder. Studies conducted in RTT patients and murine models have shown altered expression of N-methyl-D-aspartate receptors (NMDARs). Genetic deletion of the NMDAR subunit, GluN2A, in mice lacking Mecp2 is sufficient to prevent RTT phenotypes, including regression of vision.

Methods: We performed a systematic, randomized preclinical trial of chronic administration of low-dose (8 mg/kg, intraperitoneal) ketamine, an NMDAR antagonist, starting either early in development or at the onset of RTT phenotype in Mecp2-null mice.

Results: Daily exposure to ketamine ameliorated RTT symptoms and extended the life span of treated Mecp2-null mice without adverse side effects. Furthermore, significant improvement was observed in cortical processing and connectivity, which were fully restored to a wild-type level, particularly when treatment was started at the onset of regression.

Conclusions: Our findings provide strong evidence that targeting NMDA receptors can be a safe and effective treatment for RTT.

Keywords: Behavior; Breathing; Cortical activity; Parvalbumin connectivity; Preclinical trial; Survival.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • GABAergic Neurons / drug effects
  • GABAergic Neurons / metabolism
  • Ketamine / administration & dosage*
  • Ketamine / pharmacokinetics
  • Ketamine / therapeutic use
  • Methyl-CpG-Binding Protein 2 / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / drug effects
  • Neurons / physiology
  • Parvalbumins / metabolism
  • Phenotype
  • Photic Stimulation
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / metabolism
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Respiration / drug effects
  • Rett Syndrome / drug therapy
  • Rett Syndrome / physiopathology*
  • Survival Analysis
  • Visual Acuity / drug effects
  • Visual Cortex / drug effects
  • Visual Cortex / physiopathology


  • Mecp2 protein, mouse
  • Methyl-CpG-Binding Protein 2
  • Parvalbumins
  • Receptors, N-Methyl-D-Aspartate
  • Ketamine