Reversal of Neurological Defects in a Mouse Model of Rett Syndrome

By Jacky Guy, J. Gan, Jim Selfridge, S. Cobb, A. Bird. Science, 2007

1,243 citations recorded by the source corpus.

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.

Subfields: Cognitive Neuroscience, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/05bfe745ffa84bdcbfb77ff440860e80bc597f78

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Citations in the corpus

Epigenetic regulation in psychiatric disorders (2007, background): “An encouraging recent finding is that reversal of an MeCP2 deficit in mice, even after Rett-like symptoms appear, can reverse many of these symptom”
A model for neural development and treatment of Rett Syndrome using human induced pluripotent stem cells (2010, background): “Recent studies have shown that re-activation of MeCP2 expression knockout mice led to a prolonged life span and delayed onset or reversal of certain neurological symptoms (Giacometti et al., 2007; Guy et al., 2007).”
X-inactivation, imprinting, and long noncoding RNAs in health and disease. (2013, background): “Intriguingly, mouse models have shown that restoration of MECP2 expression after disease first becomes symptomatic can reverse the neurologic defects (Giacometti et al., 2007; Guy et al., 2007).”
Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state (2010, background): “This dependence may account for the remarkable reversibility of severe neurological symptoms in mice when MeCP2 is restored following development under MeCP2-deficient conditions (Guy et al., 2007).”
Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities and core autism-related deficits (2011, positive): “Recent studies in mouse models are very encouraging in this regard, including Rett syndrome (Guy et al., 2007), fragile X syndrome (Dölen et al.”
The story of Rett syndrome: from clinic to neurobiology. (2007, positive): “Recent work by Guy et al. (2007) and Giacometti et al. (2007) provide evidence supporting the feasibility of disease reversibility in mouse models of RTT. Guy et al. created a mouse in which endogenous Mecp2 is silenced by insertion of a Lox-Stop cassette and can be conditionally activated through…”
Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. (2012, methodology): “Silencing of Mecp2 in mice using a lox-Stop-lox cassette causes RTT-like features to be reversed if the expression of MeCP2 is induced in adult animals (Giacometti et al. 2007; Guy et al. 2007).”
Interneuron dysfunction in psychiatric disorders (2012, background): “In the case of Rett's syndrome, for example, restoring MECP2 function after brain development or generally enhancing synaptic maturation might be sufficient to ameliorate neurological symptoms, as shown in animal model”