Chronic Administration of the N-Methyl-D-Aspartate Receptor Antagonist Ketamine Improves Rett Syndrome Phenotype
Open accessAbstract
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.
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Ketamine treatment normalizes cortical activity in both young adults and adult mice.
“Ketamine treatment normalizes cortical activity in both young adults and adult mice 131,132 ,”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [131]
Disinhibition of pyramidal cells through low (subanesthetic) doses of ketamine normalizes inhibitory connectivity, prevents the silencing of cortical circuits, and extends the lifespan of Mecp2 mutants.
“Preclinical studies have shown that disinhibition of pyramidal cells through low (subanesthetic) doses of ketamine, an NMDAR antagonist that acts preferentially on PV+ interneurons reducing the excitatory drive onto these cells 130 , normalizes inhibitory connectivity, prevents the silencing of cortical circuits, and extends the lifespan of Mecp2 mutants 131 .”
From Developmental timing and critical windows for the treatment of psychiatric disorders (2016) · cites this paper as [131]
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MeCP2 prevents against sustained ketamine-induced synaptic depression at inhibitory synapses
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- Authors
- Patrizi, A., Picard, N., Simon, A. J., Gunner, G., Centofante, E., Andrews, N. A., & Fagiolini, M.
- Affiliations
- Boston Children's Hospital (US)
- Corresponding author
- Fagiolini, Michela
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 79
- Issue
- 9
- Pages
- 755-764
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC7410367
- OpenAlex
- W2196193533
- Cited by
- 100
- References
- 6
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 6 · 2023: 16 · 2022: 11 · 2021: 7 · 2020: 16 · 2019: 8 · 2018: 5 · 2017: 10 · 2016: 8
- FWCI
- 5.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- Simons Foundation
- International Rett Syndrome Foundation
- National Institutes of Health (NIHP30‐HD 18655)
- Intellectual and Developmental Disabilities Research Center (HD18655)
- National Institute of Neurological Disorders and Stroke (R21NS062277, R01NS070300, R01NS095959)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD018655, P30HD-18655)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- Rett syndrome, ketamine, NMDA receptor antagonism, MeCP2, Mecp2-null mice, GluN2A, cortical connectivity, treatment efficacy, lifespan extension, early treatment initiation
- MeSH terms
- Animals, Disease Models, Animal, Ketamine, Mice, Inbred C57BL, Neurons, Parvalbumins, Phenotype, Photic Stimulation, Respiration, Visual Acuity, Visual Cortex, Rett Syndrome, Survival Analysis, Receptors, N-Methyl-D-Aspartate, Pyramidal Cells, Mice, Knockout, Mice, Methyl-CpG-Binding Protein 2, GABAergic Neurons
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