title: Chronic Administration of the N-Methyl-D-Aspartate Receptor Antagonist Ketamine Improves Rett Syndrome Phenotype.
abstract: 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.
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Annarita
authors.initials: A
authors.lastname: Patrizi
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Picard
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Alex Joseph
authors.initials: AJ
authors.lastname: Simon
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Georgia
authors.initials: G
authors.lastname: Gunner
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Centofante
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Nick Arthur
authors.initials: NA
authors.lastname: Andrews
authors.affiliation: F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: michela.fagiolini@childrens.harvard.edu.
authors.forename: Michela
authors.initials: M
authors.lastname: Fagiolini
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism; D007649:Ketamine / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010320:Parvalbumins / Q000378:metabolism; D010641:Phenotype; D010775:Photic Stimulation; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012119:Respiration / Q000187:drug effects; D015518:Rett Syndrome / Q000188:drug therapy / Q000503:physiopathology*; D016019:Survival Analysis; D014792:Visual Acuity / Q000187:drug effects; D014793:Visual Cortex / Q000187:drug effects / Q000503:physiopathology
chemical_list: C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D010320:Parvalbumins; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine
keywords: Behavior; Breathing; Cortical activity; Parvalbumin connectivity; Preclinical trial; Survival