Chahrour, M. & Zoghbi, H. Y. The story of Rett syndrome: from clinic to neurobiology. Neuron 56, 422–437 (2007).
Laurvick, C. L. et al. Rett syndrome in Australia: a review of the epidemiology. J. Pediatr. 148, 347–352 (2006).
Trappe, R. et al. MECP2 mutations in sporadic cases of Rett syndrome are almost exclusively of paternal origin. Am. J. Hum. Genet. 68, 1093–1101 (2001).
Neul, J. L. et al. Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome. Neurology 70, 1313–1321 (2008).
Neul, J. L. et al. Rett syndrome: revised diagnostic criteria and nomenclature. Ann. Neurol. 68, 944–950 (2010).
Schüle, B., Armstrong, D. D., Vogel, H., Oviedo, A. & Francke, U. Severe congenital encephalopathy caused by MECP2 null mutations in males: central hypoxia and reduced neuronal dendritic structure. Clin. Genet. 74, 116–126 (2008).
Lewis, J. D. et al. Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell 69, 905–914 (1992).
Chahrour, M. et al. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320, 1224–1229 (2008).
Cheng, T. L. et al. MeCP2 suppresses nuclear microRNA processing and dendritic growth by regulating the DGCR8/Drosha complex. Dev. Cell 28, 547–560 (2014).
Dolce, A. et al. Rett syndrome and epilepsy: an update for child neurologists. Pediatr. Neurol. 48, 337–345 (2013).
Leonard, H., Cobb, S. & Downs, J. Clinical and biological progress over 50 years in Rett syndrome. Nat. Rev. Neurol. 13, 37–51 (2016).
von Tetzchner, S. et al. Vision, cognition and developmental characteristics of girls and women with Rett syndrome. Dev. Med. Child Neurol. 38, 212–225 (1996).
LeBlanc, J. J. et al. Visual evoked potentials detect cortical processing deficits in Rett syndrome. Ann. Neurol. 78, 775–786 (2015).
Neul, J. L. The relationship of Rett syndrome and MECP2 disorders to autism. Dialogues Clin. Neurosci. 14, 253–262 (2012).
American Psychiatric Association (eds). Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (American Psychiatric Publishing, 2013).
Armstrong, D., Dunn, J. K., Antalffy, B. & Trivedi, R. Selective dendritic alterations in the cortex of Rett syndrome. J. Neuropathol. Exp. Neurol. 54, 195–201 (1995).
Carter, J. C. et al. Selective cerebral volume reduction in Rett Syndrome: a multiple-approach MR imaging study. AJNR Am. J. Neuroradiol. 29, 436–441 (2008).
Amir, R. E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23, 185–188 (1999).
Chen, R. Z., Akbarian, S., Tudor, M. & Jaenisch, R. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nat. Genet. 27, 327–331 (2001).
Guy, J., Hendrich, B., Holmes, M., Martin, J. E. & Bird, A. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat. Genet. 27, 322–326 (2001).
Ward, C. S. et al. MeCP2 is critical within HoxB1-derived tissues of mice for normal lifespan. J. Neurosci. 31, 10359–10370 (2011).
Huang, T.-W. et al. Progressive changes in a distributed neural circuit underlie breathing abnormalities in mice lacking MeCP2. J. Neurosci. 36, 5572–5586 (2016).
Samaco, R. C. et al. Loss of MeCP2 in aminergic neurons causes cell-autonomous defects in neurotransmitter synthesis and specific behavioral abnormalities. Proc. Natl Acad. Sci. USA 106, 21966–21971 (2009).
Chao, H.-T. et al. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature 468, 263–269 (2010). This study shows that mice with Mecp2 deleted only in GABAergic neurons recapitulate many of the deficits observed in global knockout mice, suggesting that MeCP2 is crucial for the normal function of GABAergic neurons and that the dysfunction of GABAergic neurons contributes to RTT phenotypes.
Lioy, D. T. et al. A role for glia in the progression of Rett’s syndrome. Nature 475, 497–500 (2011). This paper shows that expression of MeCP2 exclusively in astrocytes rescues some of the major deficits in MeCP2-deficient mice, suggesting that MeCP2 does not function only in neurons and has non-cell-autonomous effects.
Derecki, N. C. et al. Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature 484, 105–109 (2012).
Wang, J. et al. Wild-type microglia do not reverse pathology in mouse models of Rett syndrome. Nature 521, E1–E4 (2015).
Schafer, D. P. et al. Microglia contribute to circuit defects in Mecp2 null mice independent of microglia-specific loss of Mecp2 expression. eLife 5, e15224 (2016).
Tropea, D. et al. Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice. Proc. Natl Acad. Sci. USA 106, 2029–2034 (2009). This paper shows that systemic treatment of MeCP2-mutant mice with a truncated form of IGF1 restores excitatory synapses and improves neurological deficits.
Fukuda, T., Itoh, M., Ichikawa, T., Washiyama, K. & Goto, Y. Delayed maturation of neuronal architecture and synaptogenesis in cerebral cortex of Mecp2-deficient mice. J. Neuropathol. Exp. Neurol. 64, 537–544 (2005).
Smrt, R. D. et al. Mecp2 deficiency leads to delayed maturation and altered gene expression in hippocampal neurons. Neurobiol. Dis. 27, 77–89 (2007).
Cohen, S. & Greenberg, M. E. Communication between the synapse and the nucleus in neuronal development, plasticity, and disease. Annu. Rev. Cell Dev. Biol. 24, 183–209 (2008).
Nelson, S. B. & Valakh, V. Excitatory/inhibitory balance and circuit homeostasis in autism spectrum disorders. Neuron 87, 684–698 (2015).
Shahbazian, M. D., Antalffy, B., Armstrong, D. L. & Zoghbi, H. Y. Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation. Hum. Mol. Genet. 11, 115–124 (2002).
Kishi, N. & Macklis, J. D. MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions. Mol. Cell Neurosci. 27, 306–321 (2004).
Fehr, S. et al. Altered attainment of developmental milestones influences the age of diagnosis of Rett syndrome. J. Child Neurol. 26, 980–987 (2011).
Einspieler, C., Kerr, A. M. & Prechtl, H. F. R. Is the early development of girls with Rett disorder really normal? Pediatr. Res. 57, 696–700 (2005).
Einspieler, C., Kerr, A. M. & Prechtl, H. F. R. Abnormal general movements in girls with Rett disorder: the first four months of life. Brain Dev. 27, S8–S13 (2005).
Marschik, P. B. et al. Changing the perspective on early development of Rett syndrome. Res. Dev. Disabil. 34, 1236–1239 (2013).
Neul, J. L. et al. Developmental delay in Rett syndrome: data from the natural history study. J. Neurodev. Disord. 6, 20 (2014).
Mellios, N. et al. MeCP2-regulated miRNAs control early human neurogenesis through differential effects on ERK and AKT signaling. Mol. Psychiatry 23, 1051–1065 (2018). This study examines cerebral organoids of iPSC-derived cells from individuals with RTT, showing dysregulation of miR-199 and miR-214 signalling and early developmental defects.
Bedogni, F. et al. Defects during Mecp2 null embryonic cortex development precede the onset of overt neurological symptoms. Cereb. Cortex 26, 2517–2529 (2016).
Kim, K. Y., Hysolli, E. & Park, I. H. Neuronal maturation defect in induced pluripotent stem cells from patients with Rett syndrome. Proc. Natl Acad. Sci. USA 108, 14169–14174 (2011).
Tsujimura, K., Abematsu, M., Kohyama, J., Namihira, M. & Nakashima, K. Neuronal differentiation of neural precursor cells is promoted by the methyl-CpG-binding protein MeCP2. Exp. Neurol. 219, 104–111 (2009).
Stancheva, I. et al. A mutant form of MeCP2 protein associated with human Rett syndrome cannot be displaced from methylated DNA by notch in Xenopus embryos. Mol. Cell 12, 425–435 (2003).
Gao, H. et al. Mecp2 regulates neural cell differentiation by suppressing the Id1 to Her2 axis in zebrafish. J. Cell Sci. 128, 2340–2350 (2015).
Guy, J., Gan, J., Selfridge, J., Cobb, S. & Bird, A. Reversal of neurological defects in a mouse model of Rett syndrome. Science 315, 1143–1147 (2007).
Giacometti, E., Luikenhuis, S., Beard, C. & Jaenisch, R. Partial rescue of MeCP2 deficiency by postnatal activation of MeCP2. Proc. Natl Acad. Sci. USA 104, 1931–1936 (2007).
McGraw, C. M., Samaco, R. C. & Zoghbi, H. Y. Adult neural function requires MeCP2. Science 333, 186 (2011).
Nguyen, M. V. C. et al. MeCP2 is critical for maintaining mature neuronal networks and global brain anatomy during late stages of postnatal brain development and in the mature adult brain. J. Neurosci. 32, 10021–10034 (2012).
Du, F. et al. Acute and crucial requirement for MeCP2 function upon transition from early to late adult stages of brain maturation. Hum. Mol. Genet. 25, 1690–1702 (2016).
Swiech, L. et al. In vivo interrogation of gene function in the mammalian brain using CRISPR-Cas9. Nat. Biotechnol. 33, 102–106 (2014).
Lyst, M. J. & Bird, A. Rett syndrome: a complex disorder with simple roots. Nat. Rev. Genet. 16, 261–275 (2015).
Meehan, R., Lewis, J. D. & Bird, A. P. Characterization of MECP2, a vertebrate DNA binding protein with affinity for methylated DNA. Nucleic Acids Res. 20, 5085–5092 (1992).
Nan, X. et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386–389 (1998).
Kinde, B., Gabel, H. W., Gilbert, C. S., Griffith, E. C. & Greenberg, M. E. Reading the unique DNA methylation landscape of the brain: non-CpG methylation, hydroxymethylation, and MeCP2. Proc. Natl Acad. Sci. USA 112, 6800–6806 (2015).
Lagger, S. et al. MeCP2 recognizes cytosine methylated tri-nucleotide and di-nucleotide sequences to tune transcription in the mammalian brain. PLoS Genet. 13, e1006793 (2017).
Guo, J. U. et al. Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain. Nat. Neurosci. 17, 215–222 (2013).
Gabel, H. W. et al. Disruption of DNA-methylation-dependent long gene repression in Rett syndrome. Nature 522, 89–93 (2015). This paper demonstrates that MeCP2 binds to mCA sites and this binding represses the expression of long genes.
Kinde, B., Wu, D. Y., Greenberg, M. E. & Gabel, H. W. DNA methylation in the gene body influences MeCP2-mediated gene repression. Proc. Natl Acad. Sci. USA 113, 15114–15119 (2016).
Stroud, H. et al. Early-life gene expression in neurons modulates lasting epigenetic states. Cell 171, 1151–1164.e16 (2017). This study shows that DNMT3A specifies the pattern of DNA methylation at CA sites, which in turn directs the binding of MeCP2 and regulates the transcription of genes.
Mellén, M., Ayata, P., Dewell, S., Kriaucionis, S. & Heintz, N. MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Cell 151, 1417–1430 (2012).
Mellén, M., Ayata, P. & Heintz, N. 5-Hydroxymethylcytosine accumulation in postmitotic neurons results in functional demethylation of expressed genes. Proc. Natl Acad. Sci. USA 114, E7812–E7821 (2017).
Skene, P. J. et al. Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state. Mol. Cell 37, 457–468 (2010).
Shah, R. R. & Bird, A. P. MeCP2 mutations: progress towards understanding and treating Rett syndrome. Genome Med. 9, 17 (2017).
Sugino, K. et al. Cell-type-specific repression by methyl-CpG-binding protein 2 is biased toward long genes. J. Neurosci. 34, 12877–12883 (2014).
Johnson, B. S. et al. Biotin tagging of MeCP2 in mice reveals contextual insights into the Rett syndrome transcriptome. Nat. Med. 23, 1203–1214 (2017).
Lyst, M. J. et al. Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor. Nat. Neurosci. 16, 898–902 (2013).This study identifies the NID in MeCP2 and demonstrates that RTT-causing mutations in the NID abolish the interaction between MeCP2 and the NCoR–SMRT co-repressor complexes.
Kruusvee, V. et al. Structure of the MeCP2-TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders. Proc. Natl Acad. Sci. USA 114, E3243–E3250 (2017).
Tillotson, R. et al. Radically truncated MeCP2 rescues Rett syndrome-like neurological defects. Nature 550, 398–401 (2017). This study establishes that truncated MeCP2 protein retaining only the MBD and NID is able to rescue neurological symptoms when introduced into MeCP2-deficient mice.
Ebert, D. H. et al. Activity-dependent phosphorylation of MECP2 T308 regulates interaction with NCoR. Nature 499, 341–345 (2013).
Ben-Shachar, S., Chahrour, M., Thaller, C., Shaw, C. A. & Zoghbi, H. Y. Mouse models of MeCP2 disorders share gene expression changes in the cerebellum and hypothalamus. Hum. Mol. Genet. 18, 2431–2442 (2009).
Tudor, M., Akbarian, S., Chen, R. Z. & Jaenisch, R. Transcriptional profiling of a mouse model for Rett syndrome reveals subtle transcriptional changes in the brain. Proc. Natl Acad. Sci. USA 99, 15536–15541 (2002).
Li, Y. et al. Global transcriptional and translational repression in human-embryonic-stem-cell-derived Rett syndrome neurons. Cell Stem Cell 13, 446–458 (2013). This study inactivates MECP2 in human iPSC-derived neurons and shows a global alteration of RNA transcripts.
Nott, A. et al. Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior. Nat. Neurosci. 19, 1497–1505 (2016).
Ciernia, A. V. & LaSalle, J. The landscape of DNA methylation amid a perfect storm of autism aetiologies. Nat. Rev. Neurosci. 17, 411–423 (2016).
Baker, S. A. et al. An AT-hook domain in MeCP2 determines the clinical course of Rett syndrome and related disorders. Cell 152, 984–996 (2013).
Heckman, L. D., Chahrour, M. H. & Zoghbi, H. Y. Rett-causing mutations reveal two domains critical for MeCP2 function and for toxicity in MECP2 duplication syndrome mice. eLife 3, e02676 (2014).
Nan, X. et al. Interaction between chromatin proteins MECP2 and ATRX is disrupted by mutations that cause inherited mental retardation. Proc. Natl Acad. Sci. USA 104, 2709–2714 (2007).
Krol, J., Loedige, I. & Filipowicz, W. The widespread regulation of microRNA biogenesis, function and decay. Nat. Rev. Genet. 11, 597–610 (2010).
Mellios, N. & Sur, M. The emerging role of microRNAs in schizophrenia and autism spectrum disorders. Front. Psychiatry 3, 39 (2012).
Wu, H. et al. Genome-wide analysis reveals methyl-CpG-binding protein 2-dependent regulation of microRNAs in a mouse model of Rett syndrome. Proc. Natl Acad. Sci. USA 107, 18161–18166 (2010).
Urdinguio, R. G. et al. Disrupted microRNA expression caused by Mecp2 loss in a mouse model of Rett syndrome. Epigenetics 5, 656–663 (2010).
Mellios, N. et al. β2-Adrenergic receptor agonist ameliorates phenotypes and corrects microRNA-mediated IGF1 deficits in a mouse model of Rett syndrome. Proc. Natl Acad. Sci. USA 111, 9947–9952 (2014).
Klein, M. E. et al. Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA. Nat. Neurosci. 10, 1513–1514 (2007).
Nomura, T. et al. MeCP2-dependent repression of an imprinted miR-184 released by depolarization. Hum. Mol. Genet. 17, 1192–1199 (2008).
Gao, Y. et al. Inhibition of miR-15a promotes BDNF expression and rescues dendritic maturation deficits in MeCP2-deficient neurons. Stem Cells 33, 1618–1629 (2015).
Szulwach, K. E. et al. Cross talk between microRNA and epigenetic regulation in adult neurogenesis. J. Cell Biol. 189, 127–141 (2010).
Chen, Y., Shin, B. C., Thamotharan, S. & Devaskar, S. U. Differential methylation of the micro-RNA 7b gene targets postnatal maturation of murine neuronal Mecp2 gene expression. Dev. Neurobiol. 74, 407–425 (2014).
Smrt, R. D. et al. MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1. Stem Cells 28, 1060–1070 (2010).
Davis, B. N., Hilyard, A. C., Lagna, G. & Hata, A. SMAD proteins control DROSHA-mediated microRNA maturation. Nature 454, 56–61 (2008).
Li, H., Zhong, X., Chau, K. F., Williams, E. C. & Chang, Q. Loss of activity-induced phosphorylation of MeCP2 enhances synaptogenesis, LTP and spatial memory. Nat. Neurosci. 14, 1001–1008 (2011).
Huang, Y.-W. A., Ruiz, C. R., Eyler, E. C. H., Lin, K. & Meffert, M. K. Dual regulation of miRNA biogenesis generates target specificity in neurotrophin-induced protein synthesis. Cell 148, 933–946 (2012).
Piskounova, E. et al. Lin28A and Lin28B inhibit let-7 microRNA biogenesis by distinct mechanisms. Cell 147, 1066–1079 (2011).
Han, K. et al. Human-specific regulation of MeCP2 levels in fetal brains by microRNA miR-483-5p. Genes Dev. 27, 485–490 (2013).
Rodrigues, D. C. et al. MECP2 is post-transcriptionally regulated during human neurodevelopment by combinatorial action of RNA-binding proteins and miRNAs. Cell Rep. 17, 720–734 (2016).
Zhang, Y. et al. MiR-130a regulates neurite outgrowth and dendritic spine density by targeting MeCP2. Protein Cell 7, 489–500 (2016).
Im, H. I., Hollander, J. A., Bali, P. & Kenny, P. J. MeCP2 controls BDNF expression and cocaine intake through homeostatic interactions with microRNA-212. Nat. Neurosci. 13, 1120–1127 (2010).
Dani, V. S. et al. Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome. Proc. Natl Acad. Sci. USA 102, 12560–12565 (2005).
Nelson, E. D., Kavalali, E. T. & Monteggia, L. M. MeCP2-dependent transcriptional repression regulates excitatory neurotransmission. Curr. Biol. 16, 710–716 (2006).
Banerjee, A. et al. Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome. Proc. Natl Acad. Sci. USA 113, E7287–E7296 (2016). This study shows that visually driven excitatory and inhibitory conductances are both reduced in MeCP2-deficient mice in vivo, and that PV
-cell-specific MeCP2 deletion recapitulates effects of global MeCP2 deletion on cortical circuits.
Calfa, G., Li, W., Rutherford, J. M. & Pozzo-Miller, L. Excitation/inhibition imbalance and impaired synaptic inhibition in hippocampal area CA3 of Mecp2 knockout mice. Hippocampus 25, 159–168 (2015).
Taneja, P. et al. Pathophysiology of locus ceruleus neurons in a mouse model of Rett syndrome. J. Neurosci. 29, 12187–12195 (2009).
Abdala, A. P. L., Dutschmann, M., Bissonnette, J. M. & Paton, J. F. R. Correction of respiratory disorders in a mouse model of Rett syndrome. Proc. Natl Acad. Sci. USA 107, 18208–18213 (2010).
Medrihan, L. et al. Early defects of GABAergic synapses in the brain stem of a MeCP2 mouse model of Rett syndrome. J. Neurophysiol. 99, 112–121 (2008).
Kron, M. et al. Brain activity mapping in Mecp2 mutant mice reveals functional deficits in forebrain circuits, including key nodes in the default mode network, that are reversed with ketamine treatment. J. Neurosci. 32, 13860–13872 (2012).
Calfa, G. et al. Network hyperexcitability in hippocampal slices from Mecp2 mutant mice revealed by voltage-sensitive dye imaging. J. Neurophysiol. 105, 1768–1784 (2011).
Mo, A. et al. Epigenomic signatures of neuronal diversity in the mammalian brain. Neuron 86, 1369–1384 (2015).
Durand, S. et al. NMDA receptor regulation prevents regression of visual cortical function in the absence of Mecp2. Neuron 76, 1078–1090 (2012).
Meng, X. et al. Manipulations of MeCP2 in glutamatergic neurons highlight their contributions to Rett and other neurological disorders. eLife 5, e14199 (2016).
Gemelli, T. et al. Postnatal loss of methyl-CpG binding protein 2 in the forebrain is sufficient to mediate behavioral aspects of Rett syndrome in mice. Biol. Psychiatry 59, 468–476 (2006).
Ure, K. et al. Restoration of Mecp2 expression in GABAergic neurons is sufficient to rescue multiple disease features in a mouse model of Rett syndrome. eLife 5, e14198 (2016).
Rudy, B., Fishell, G., Lee, S. H. & Hjerling-Leffler, J. Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons. Dev. Neurobiol. 71, 45–61 (2011).
Kepecs, A. & Fishell, G. Interneuron cell types are fit to function. Nature 505, 318–326 (2014).
Fishell, G. & Rudy, B. Mechanisms of inhibition within the telencephalon: ‘where the wild things are’. Annu. Rev. Neurosci. 34, 535–567 (2011).
Pfeffer, C. K., Xue, M., He, M., Huang, Z. J. & Scanziani, M. Inhibition of inhibition in visual cortex: the logic of connections between molecularly distinct interneurons. Nat. Neurosci. 16, 1068–1076 (2013).
Adesnik, H., Bruns, W., Taniguchi, H., Huang, Z. J. & Scanziani, M. A neural circuit for spatial summation in visual cortex. Nature 490, 226–231 (2012).
Gentet, L. J. et al. Unique functional properties of somatostatin-expressing GABAergic neurons in mouse barrel cortex. Nat. Neurosci. 15, 607–612 (2012).
Lee, S., Kruglikov, I., Huang, Z. J., Fishell, G. & Rudy, B. A disinhibitory circuit mediates motor integration in the somatosensory cortex. Nat. Neurosci. 16, 1662–1670 (2013).
Olsen, S. R., Bortone, D. S., Adesnik, H. & Scanziani, M. Gain control by layer six in cortical circuits of vision. Nature 483, 47–52 (2012).
Wilson, N. R., Runyan, C. A., Wang, F. L. & Sur, M. Division and subtraction by distinct cortical inhibitory networks in vivo. Nat. Biotechnol. 488, 343–348 (2012).
Xue, M., Atallah, B. V. & Scanziani, M. Equalizing excitation-inhibition ratios across visual cortical neurons. Nature 511, 596–600 (2014).
Ito-Ishida, A., Ure, K., Chen, H., Swann, J. W. & Zoghbi, H. Y. Loss of MeCP2 in parvalbumin-and somatostatin-expressing neurons in mice leads to distinct Rett syndrome-like phenotypes. Neuron 88, 651–658 (2015).
Krishnan, K. et al. MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex. Proc. Natl Acad. Sci. USA 112, E4782–E4791 (2015).
Mierau, S. B., Patrizi, A., Hensch, T. K. & Fagiolini, M. Cell-specific regulation of N-methyl-d-aspartate receptor maturation by Mecp2 in cortical circuits. Biol. Psychiatry 79, 746–754 (2016).
He, L. J. et al. Conditional deletion of Mecp2 in parvalbumin-expressing GABAergic cells results in the absence of critical period plasticity. Nat. Commun. 5, 5036 (2014).
Tang, X. et al. KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome. Proc. Natl Acad. Sci. USA 113, 751–756 (2016).
Blaesse, P., Airaksinen, M. S., Rivera, C. & Kaila, K. Cation–chloride cotransporters and neuronal function. Neuron 61, 820–838 (2009).
Kaila, K., Price, T. J., Payne, J. A., Puskarjov, M. & Voipio, J. Cation–chloride cotransporters in neuronal development, plasticity and disease. Nat. Rev. Neurosci. 15, 637–654 (2014).
Ben-Ari, Y. NKCC1 chloride importer antagonists attenuate many neurological and psychiatric disorders. Trends Neurosci. 40, 536–554 (2017).
He, Q. E., Nomura, T., Xu, J. & Contractor, A. The developmental switch in GABA polarity is delayed in fragile X mice. Eur. J. Neurosci. 34, 446–450 (2014).
Ben-Ari, Y. et al. Refuting the challenges of the developmental shift of polarity of GABA actions: GABA more exciting than ever! Front. Cell. Neurosci. 6, 35 (2012).
Duarte, S. T. et al. Abnormal expression of cerebrospinal fluid cation chloride cotransporters in patients with Rett syndrome. PLoS ONE 8, e68851 (2013).
Castro, J. et al. Functional recovery with recombinant human IGF1 treatment in a mouse model of Rett Syndrome. Proc. Natl Acad. Sci. USA 111, 9941–9946 (2014).
Kelsch, W. et al. Insulin-like growth factor 1 and a cytosolic tyrosine kinase activate chloride outward transport during maturation of hippocampal neurons. Eur. J. Neurosci. 21, 8339–8347 (2001).
Ko, H. et al. The emergence of functional microcircuits in visual cortex. Nature 496, 96–100 (2013).
Espinosa, J. S. & Stryker, M. P. Development and plasticity of the primary visual cortex. Neuron 75, 230–249 (2012).
Chen, S. X., Kim, A. N., Peters, A. J. & Komiyama, T. Subtype-specific plasticity of inhibitory circuits in motor cortex during motor learning. Nat. Neurosci. 18, 1109–1115 (2015).
Cichon, J. & Gan, W.-B. Branch-specific dendritic Ca2+ spikes cause persistent synaptic plasticity. Nature 520, 180–185 (2015).
Hayashi-Takagi, A. et al. Labelling and optical erasure of synaptic memory traces in the motor cortex. Nature 525, 333–338 (2015).
Turrigiano, G. G. & Nelson, S. B. Homeostatic plasticity in the developing nervous system. Nat. Rev. Neurosci. 5, 97–107 (2004).
Sur, M., Nagakura, I., Chen, N. & Sugihara, H. Mechanisms of plasticity in the developing and adult visual cortex. Prog. Brain Res. 207, 243–254 (2013).
Hong, E. J., McCord, A. E. & Greenberg, M. E. A. Biological function for the neuronal activity-dependent component of Bdnf transcription in the development of cortical inhibition. Neuron 60, 610–624 (2008).
Yee, A. X., Hsu, Y.-T. & Chen, L. A metaplasticity view of the interaction between homeostatic and Hebbian plasticity. Philos. Trans. R. Soc. Lond. B Biol. Sci. 372, 20160155 (2017).
Mullins, C., Fishell, G. & Tsien, R. W. Unifying views of autism spectrum disorders: a consideration of autoregulatory feedback loops. Neuron 89, 1131–1156 (2016).
Ebert, D. H. & Greenberg, M. E. Activity-dependent neuronal signalling and autism spectrum disorder. Nature 493, 327–337 (2013).
Blackman, M. P., Djukic, B., Nelson, S. B. & Turrigiano, G. G. A critical and cell-autonomous role for MeCP2 in synaptic scaling up. J. Neurosci. 32, 13529–13536 (2012).
Qiu, Z. et al. The Rett syndrome protein MeCP2 regulates synaptic scaling. J. Neurosci. 32, 989–994 (2012).
Zhong, X., Li, H. & Chang, Q. MeCP2 phosphorylation is required for modulating synaptic scaling through mGluR5. J. Neurosci. 32, 12841–12847 (2012).
Noutel, J., Hong, Y. K., Leu, B., Kang, E. & Chen, C. Experience-dependent retinogeniculate synapse remodeling is abnormal in MeCP2-deficient mice. Neuron 70, 35–42 (2011).
Tropea, D., Van Wart, A. & Sur, M. Molecular mechanisms of experience-dependent plasticity in visual cortex. Philos. Trans. R. Soc. Lond. B Biol. Sci. 364, 341–355 (2009).
Brown, K. et al. The molecular basis of variable phenotypic severity among common missense mutations causing Rett syndrome. Hum. Mol. Genet. 25, 558–570 (2016).
Samaco, R. C. et al. Crh and Oprm1 mediate anxiety-related behavior and social approach in a mouse model of MECP2 duplication syndrome. Nat. Genet. 44, 206–211 (2012).
Sztainberg, Y. et al. Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides. Nature 528, 123–126 (2015).
Van Esch, H. et al. Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males. Am. J. Hum. Genet. 77, 442–453 (2005).
Samaco, R. C. et al. Female Mecp2
+/− mice display robust behavioral deficits on two different genetic backgrounds providing a framework for pre-clinical studies. Hum. Mol. Genet. 22, 96–109 (2013).
Goffin, D. et al. Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses. Nat. Neurosci. 15, 274–283 (2011).
Lamonica, J. M. et al. Elevating expression of MeCP2 T158M rescues DNA binding and Rett syndrome-like phenotypes. J. Clin. Invest. 127, 1889–1904 (2017).
Veeraragavan, S. et al. Loss of MeCP2 in the rat models regression, impaired sociability and transcriptional deficits of Rett syndrome. Hum. Mol. Genet. 25, 3284–3302 (2016).
Chen, Y. et al. Modeling Rett syndrome using TALEN-edited MECP2 mutant cynomolgus monkeys. Cell 169, 945–955.e10 (2017).
Khwaja, O. S. et al. Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome. Proc. Natl Acad. Sci. USA 111, 4596–4601 (2014).
Li, W. & Pozzo-Miller, L. BDNF deregulation in Rett syndrome. Neuropharmacology 76, 737–746 (2014).
Katz, D. M. et al. Rett syndrome: crossing the threshold to clinical translation. Trends Neurosci. 39, 100–113 (2016).
Chang, Q., Khare, G., Dani, V., Nelson, S. & Jaenisch, R. The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression. Neuron 49, 341–348 (2006).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02061137 (2014).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02153723 (2014).
El-Husseini, A. E. D., Schnell, E., Chetkovich, D. M., Nicoll, R. A. & Bredt, D. S. PSD-95 involvement in maturation of excitatory synapses. Acta Crystallogr. B. 290, 1364–1368 (2000).
Sheng, M. & Kim, M. J. Postsynaptic signaling and plasticity mechanisms. Acta Crystallogr. B. 298, 776–780 (2002).
Yoshii, A. & Constantine-Paton, M. BDNF induces transport of PSD-95 to dendrites through PI3K-AKT signaling after NMDA receptor activation. Nat. Neurosci. 10, 702–711 (2007).
Zheng, W. H. & Quirion, R. Comparative signaling pathways of insulin-like growth factor-1 and brain-derived neurotrophic factor in hippocampal neurons and the role of the PI3 kinase pathway in cell survival. J. Neurochem. 89, 844–852 (2004).
Chao, H.-T., Zoghbi, H. Y. & Rosenmund, C. MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron 56, 58–65 (2007).
Farra, N. et al. Rett syndrome induced pluripotent stem cell-derived neurons reveal novel neurophysiological alterations. Mol. Psychiatry 17, 1261–1271 (2012).
Marchetto, M. C. N. et al. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 143, 527–539 (2010).
Williams, E. C. et al. Mutant astrocytes differentiated from Rett syndrome patients-specific iPSCs have adverse effects on wild-type neurons. Hum. Mol. Genet. 23, 2968–2980 (2014).
Yazdani, M. et al. Disease modeling using embryonic stem cells: MeCP2 regulates nuclear size and RNA synthesis in neurons. Stem Cells 30, 2128–2139 (2012).
Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (2012).
Quadrato, G. et al. Cell diversity and network dynamics in photosensitive human brain organoids. Nature 545, 48–53 (2017).
Di Lullo, E. & Kriegstein, A. R. The use of brain organoids to investigate neural development and disease. Nat. Rev. Neurosci. 18, 573–584 (2017).
Sahin, M. & Sur, M. Genes, circuits, and precision therapies for autism and related neurodevelopmental disorders. Science 350, aab3897 (2015).
Luikenhuis, S., Giacometti, E., Beard, C. F. & Jaenisch, R. Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice. Proc. Natl Acad. Sci. USA 101, 6033–6038 (2004).
Hao, S. et al. Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice. Nature 526, 430–434 (2015).
Lu, H. et al. Loss and gain of MeCP2 cause similar hippocampal circuit dysfunction that is rescued by deep brain stimulation in a Rett syndrome mouse model. Neuron 91, 739–747 (2016).
Chiken, S. & Nambu, A. Mechanism of deep brain stimulation: inhibition, excitation, or disruption? Neuroscientist 22, 313–322 (2016).
Garg, S. K. et al. Systemic delivery of MeCP2 rescues behavioral and cellular deficits in female mouse models of Rett syndrome. J. Neurosci. 33, 13612–13620 (2013).
Brendel, C. et al. Readthrough of nonsense mutations in Rett syndrome: evaluation of novel aminoglycosides and generation of a new mouse model. J. Mol. Med. 89, 389–398 (2011).
Vecsler, M. et al. Ex vivo treatment with a novel synthetic aminoglycoside NB54 in primary fibroblasts from Rett syndrome patients suppresses MECP2 nonsense mutations. PLoS ONE 6, e20733 (2011).
Sripathy, S. et al. Screen for reactivation of MeCP2 on the inactive X chromosome identifies the BMP/TGF-β superfamily as a regulator of XIST expression. Proc. Natl Acad. Sci. USA 114, 1619–1624 (2017).
Carrette, L. L. G. et al. A mixed modality approach towards Xi reactivation for Rett syndrome and other X-linked disorders. Proc. Natl Acad. Sci. USA 115, E668–E675 (2018).
Sinnamon, J. R. et al. Site-directed RNA repair of endogenous Mecp2 RNA in neurons. Proc. Natl Acad. Sci. USA 114, 201715320 (2017). This study demonstrates that site-directed RNA editing is able to repair, at the mRNA level, a RTT-causing mutation affecting the mouse MeCP2 MBD.