Reversal of Neurological Defects in a Mouse Model of Rett Syndrome
Open accessAbstract
Rett syndrome is an autism spectrum disorder caused by mosaic expression of mutant copies of the X-linked MECP2 gene in neurons. However, neurons do not die, which suggests that this is not a neurodegenerative disorder. An important question for future therapeutic approaches to this and related disorders concerns phenotypic reversibility. Can viable but defective neurons be repaired, or is the damage done during development without normal MeCP2 irrevocable? Using a mouse model, we demonstrate robust phenotypic reversal, as activation of MeCP2 expression leads to striking loss of advanced neurological symptoms in both immature and mature adult animals.
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Restoration of MeCP2 expression in symptomatic Mecp2 mutant mice reversed symptoms, improved neurological assessments and overall health, and 80% of tamoxifen-treated animals survived beyond 30 weeks of age.
“Remarkably, restoration of MeCP2 expression reversed symptoms: neurological assessments and overall health improved and 80% of TM-treated animals survived beyond 30 weeks of age (end of study).”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [145]
The passage describing the symptomatic male mice (indexed as Abstract; page unavailable) reports improved symptom scores after MeCP2 restoration and says five of six TM-treated animals survived well beyond the untreated mice’s maximum recorded lifespan of 17 weeks. It does not establish that 80% survived beyond 30 weeks of age or identify 30 weeks as the end of the study. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMany of the consequences of MeCP2 loss can be reversed by postnatal restoration of MeCP2 expression.
“while many of the consequences of MeCP2 loss can be reversed by postnatal restoration of MeCP2 expression, 11,12”
From Neonatal MeCP2 is important for the organization of sex differences in vasopressin expression (2012) · cites this paper as [11]
Developmental absence of MeCP2 does not irreversibly damage neurons.
“This pivotal finding showed that developmental absence of MeCP2 does not irreversibly damage neurons, instilling hope that symptom reversal is possible in RTT patients.”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [145]
Guy et al. achieved symptom reversal in Mecp2 mutant mice following the onset of motor dysfunction and neurological deficits.
“In a landmark study, Guy et al. achieved symptom reversal in Mecp2 mutant mice following the onset of motor dysfunction and neurological deficits.”
From Rett syndrome: a neurological disorder with metabolic components (2018) · cites this paper as [145]
Restoration of Mecp2 expression in mutant mice after the onset of symptoms rescues the neurological deficits, including motor function, and significantly prolongs survival.
“Restoration of Mecp2 expression in mutant mice after the onset of symptoms rescues the neurological deficits, including motor function, and significantly prolongs survival6.”
From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [6]
Re-expressing Mecp2 in symptomatic Mecp2 null mice dramatically improves function and longevity.
“Re-expressing Mecp2 in symptomatic Mecp2 null mice dramatically improves function and longevity, providing hope that therapeutic intervention is possible in humans.”
From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [6]
Taken together, these findings support the view that MECP2 does not necessarily play a pivotal part in brain development but may instead be required to maintain full neurological function once development has occurred.
“Taken together, these findings support the view that MECP2 does not necessarily play a pivotal part in brain development but may instead be required to maintain full neurological function once development has occurred 4 .”
From Progress toward treatments for synaptic defects in autism (2013) · cites this paper as [4]
Activation of Mecp2 in 70% of neurons in both immature and mature adult mice reversed many morphological defects in the motor cortex, including neuronal size and dendritic complexity, and led to marked improvement in respiratory and sensorimotor functions.
“activation of Mecp2 in 70% of neurons in both immature and mature adult mice reversed many morphological defects in the motor cortex, including neuronal size and dendritic complexity. This led to a marked improvement in respiratory and sensorimotor functions, including breathing pattern, grip strength and balance-beam and rotarod performance 4 .”
From Progress toward treatments for synaptic defects in autism (2013) · cites this paper as [4]
These results challenge the notion that all forms of ASD are irreversible neurodevelopmental disorders.
“These results challenge the notion that all forms of ASD are irreversible neurodevelopmental disorders 4 .”
From Progress toward treatments for synaptic defects in autism (2013) · cites this paper as [4]
Mouse models of Rett syndrome, Angelman syndrome, tuberous sclerosis complex, Fragile X syndrome, and rare SHANK mutations have provided strong evidence that interventions of a genetic or pharmacological nature can improve ASD phenotypes.
“Several mouse models of ASD, including those of Rett syndrome96,97, Angelman syndrome98, tuberous sclerosis complex71, and Fragile X23 syndrome, and mouse models of rare mutations in SHANK proteins49, have provided convincing evidence that ASD phenotypes can be improved by genetic or pharmacological interventions”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [96]
The Cre-ERt2 driver line effectively rescues gene expression in adult mice after tamoxifen administration.
“a hemizygous inducible, and ubiquitously-expressing, Cre-ERt2 driver line (Hayashi and McMahon, 2002) previously shown to effectively rescue gene expression in adult mice (Guy et al., 2007) after tamoxifen (TMX) administration.”
From Pathogenic SYNGAP1 Mutations Impair Cognitive Development by Disrupting Maturation of Dendritic Spine Synapses (2012) · cites this paper as Guy et al., 2007
Experimental interventions rescue subsets of behavioral abnormalities in mouse models of autism.
“Experimental interventions, working through diverse genetic and pharmacological mechanisms, rescue subsets of behavioral abnormalities in these mouse models (31, 43, 48–52).”
From Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism (2012) · cites this paper as [31]
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- Authors
- Guy, J., Gan, J., Selfridge, J., Cobb, S., & Bird, A.
- Affiliations
- Wellcome Centre for Cell Biology (GB)
- Corresponding author
- Bird, Adrian
- Venue
- Science
- Published
- 2007-02-23
- Volume
- 315
- Issue
- 5815
- Pages
- 1143-1147
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC7610836
- OpenAlex
- W1999775510
- Cited by
- 1,230
- References
- 15
- Citations by year
- 2026: 36 · 2025: 44 · 2024: 51 · 2023: 44 · 2022: 53 · 2021: 65 · 2020: 72 · 2019: 59 · 2018: 46 · 2017: 72 · 2016: 79 · 2015: 86 · 2014: 73 · 2013: 81 · 2012: 106
- FWCI
- 36.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Wellcome Trust (077224)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Rett syndrome, MeCP2, autism spectrum disorder, X-linked disorders, neuronal dysfunction, mouse model
- MeSH terms
- Animals, Brain, Chimera, Disease Models, Animal, Female, Gene Expression Regulation, Male, Mice, Inbred C57BL, Synaptic Transmission, Neurons, Phenotype, Tamoxifen, Rett Syndrome, Long-Term Potentiation, Gene Targeting, Transgenes, Mice, Methyl-CpG-Binding Protein 2
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