Rett Syndrome (RTT) is an X-linked neurodevelopmental disorder and the leading known genetic cause of autism in girls. RTT is characterized by normal early development followed by cognitive, motor and language regression. Mutations in the X-linked MECP2 (methyl-CpG binding protein 2) gene account for 90% of RTT cases. The neurobiology of MECP2 is fundamental to understanding the mechanisms of RTT and to the identification of therapeutics for the disorder. Mutant mice that lack MeCP2 or express a truncated MeCP2 protein recapitulate many features of RTT. Recent evidence points to the hypothesis that the deficits of RTT arise from a recoverable failure of synaptic and circuit development in the brain, and molecular analyses of cortical development and plasticity point to mechanisms that suggest a novel therapeutic strategy for the disorder. We propose two specific aims.
In aim 1, we will use a mouse model of RTT with a germline null mutation of MeCP2, to examine at multiple levels of analysis the hypothesis that a MeCP2 deficit causes synapses and circuits to remain in an immature state. First, we will quantify the brain expression of key synaptic maturation molecules that are downstream of Insulin-like Growth Factor 1 (IGF1) and Brain-derived Neurotrophic Factor (BDNF), that we hypothesize are downregulated in MeCP2 deficient mice. Second, we will use two-photon imaging of neurons and their dendrites across time in vivo to evaluate structural correlates of spine maturation. Third, we will measure functional synapse maturation and circuit plasticity through intracellular electrophysiology in vitro and optical imaging of visual cortex in vivo during experience-dependent plasticity. Fourth, we will assess the organismal physiology of the animals along metrics of maturation in central control systems, including locomotion, heart rate, respiration, and survival rates. Fifth, we will evaluate the mice on behavioral tests that characterize RTT, designed to quantify anxiety, learning and social interaction. Lastly, we will apply microarray and bioinformatics analyses to identify IGF1 related synapse maturation pathways specific to MeCP2. These measurements will provide detailed quantifications of the MeCP2 mutant phenotype and a concrete series of benchmarks for evaluating the effectiveness of the proposed treatment.
In aim 2, we will apply recombinant human IGF1 systemically, across ranges of dose and duration, to MeCP2 mutant mice to test the hypothesis that treatment with IGF1 would ameliorate symptoms of the disorder by causing synapses and circuits to rapidly mature. Since IGF1 crosses the blood-brain barrier and is approved by the FDA for pediatric use for other indications, we expect that these hypotheses, if supported, will advance the use of recombinant human IGF1 for treating Rett Syndrome.

Public Health Relevance

Rett Syndrome is a major neurodevelopmental disorder caused for the majority of cases by mutation in the X- linked MeCP2 gene for which there is no cure. We propose to investigate a novel therapy for RTT, based on the hypothesis that a peculiar characteristic in this disorder arise from persistence of immature circuitry in the brain. Since IGF1 is FDA-approved for clinical use in children with growth failure, this study represents a valid approach for a therapeutic intervention on RTT patients.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Panchision, David M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts Institute of Technology
Schools of Arts and Sciences
United States
Zip Code
Mellios, N; Feldman, D A; Sheridan, S D et al. (2018) MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling. Mol Psychiatry 23:1051-1065
Ip, Jacque P K; Nagakura, Ikue; Petravicz, Jeremy et al. (2018) Major Vault Protein, a Candidate Gene in 16p11.2 Microdeletion Syndrome, Is Required for the Homeostatic Regulation of Visual Cortical Plasticity. J Neurosci 38:3890-3900
Banerjee, Abhishek; Rikhye, Rajeev V; Breton-Provencher, Vincent et al. (2016) Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome. Proc Natl Acad Sci U S A 113:E7287-E7296
Swiech, Lukasz; Heidenreich, Matthias; Banerjee, Abhishek et al. (2015) In vivo interrogation of gene function in the mammalian brain using CRISPR-Cas9. Nat Biotechnol 33:102-6
Sahin, Mustafa; Sur, Mriganka (2015) Genes, circuits, and precision therapies for autism and related neurodevelopmental disorders. Science 350:
Mellios, Nikolaos; Woodson, Jonathan; Garcia, Rodrigo I et al. (2014) ?2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome. Proc Natl Acad Sci U S A 111:9947-52