Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Altered neuronal network and rescue in a human MECP2 duplication model

Abstract

Increased dosage of methyl-CpG-binding protein-2 (MeCP2) results in a dramatic neurodevelopmental phenotype with onset at birth. We generated induced pluripotent stem cells (iPSCs) from patients with the MECP2 duplication syndrome (MECP2dup), carrying different duplication sizes, to study the impact of increased MeCP2 dosage in human neurons. We show that cortical neurons derived from these different MECP2dup iPSC lines have increased synaptogenesis and dendritic complexity. In addition, using multi-electrodes arrays, we show that neuronal network synchronization was altered in MECP2dup-derived neurons. Given MeCP2 functions at the epigenetic level, we tested whether these alterations were reversible using a library of compounds with defined activity on epigenetic pathways. One histone deacetylase inhibitor, NCH-51, was validated as a potential clinical candidate. Interestingly, this compound has never been considered before as a therapeutic alternative for neurological disorders. Our model recapitulates early stages of the human MECP2 duplication syndrome and represents a promising cellular tool to facilitate therapeutic drug screening for severe neurodevelopmental disorders.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Van Esch H, Bauters M, Ignatius J, Jansen M, Raynaud M, Hollanders K 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 2005; 77: 442–453.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. del Gaudio D, Fang P, Scaglia F, Ward PA, Craigen WJ, Glaze DG et al. Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males. Genet Med 2006; 8: 784–792.

    Article  CAS  PubMed  Google Scholar 

  3. Ramocki MB, Peters SU, Tavyev YJ, Zhang F, Carvalho CM, Schaaf CP et al. Autism and other neuropsychiatric symptoms are prevalent in individuals with MeCP2 duplication syndrome. Ann Neurol 2009; 66: 771–782.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ramocki MB, Tavyev YJ, Peters SU . The MECP2 duplication syndrome. Am J Med Genet A 2010; 152A: 1079–1088.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Van Esch H . MECP2 Duplication Syndrome. Mol Syndromol 2012; 2: 128–136.

    CAS  PubMed  Google Scholar 

  6. Luikenhuis S, Giacometti E, Beard CF, Jaenisch R . Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice. Proc Natl Acad Sci USA 2004; 101: 6033–6038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Collins AL, Levenson JM, Vilaythong AP, Richman R, Armstrong DL, Noebels JL et al. Mild overexpression of MeCP2 causes a progressive neurological disorder in mice. Hum Mol Genet 2004; 13: 2679–2689.

    Article  CAS  PubMed  Google Scholar 

  8. Na ES, Nelson ED, Adachi M, Autry AE, Mahgoub MA, Kavalali ET et al. A mouse model for MeCP2 duplication syndrome: MeCP2 overexpression impairs learning and memory and synaptic transmission. J Neurosci 2012; 32: 3109–3117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Samaco RC, Mandel-Brehm C, McGraw CM, Shaw CA, McGill BE, Zoghbi HY . Crh and Oprm1 mediate anxiety-related behavior and social approach in a mouse model of MECP2 duplication syndrome. Nat Genet 2012; 44: 206–211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Jung BP, Jugloff DG, Zhang G, Logan R, Brown S, Eubanks JH . The expression of methyl CpG binding factor MeCP2 correlates with cellular differentiation in the developing rat brain and in cultured cells. J Neurobiol 2003; 55: 86–96.

    Article  CAS  PubMed  Google Scholar 

  11. Jiang M, Ash RT, Baker SA, Suter B, Ferguson A, Park J et al. Dendritic arborization and spine dynamics are abnormal in the mouse model of MECP2 duplication syndrome. J Neurosci 2013; 33: 19518–19533.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Chahrour M, Zoghbi HY . The story of Rett syndrome: from clinic to neurobiology. Neuron 2007; 56: 422–437.

    Article  CAS  PubMed  Google Scholar 

  13. Chailangkarn T, Acab A, Muotri AR . Modeling neurodevelopmental disorders using human neurons. Curr Opin Neurobiol 2012; 22: 785–790.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Marchetto MC, Carromeu C, Acab A, Yu D, Yeo GW, Mu Y et al. A model for neural development and treatment of Rett syndrome using human induced pluripotent stem cells. Cell 2010; 143: 527–539.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Muotri AR, Marchetto MC, Coufal NG, Oefner R, Yeo G, Nakashima K et al. L1 retrotransposition in neurons is modulated by MeCP2. Nature 2010; 468: 443–446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Carvalho CM, Zhang F, Liu P, Patel A, Sahoo T, Bacino CA et al. Complex rearrangements in patients with duplications of MECP2 can occur by fork stalling and template switching. Hum Mol Genet 2009; 18: 2188–2203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Carvalho CM, Pehlivan D, Ramocki MB, Fang P, Alleva B, Franco LM et al. Replicative mechanisms for CNV formation are error prone. Nat Genet 2013; 45: 1319–1326.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131: 861–872.

    Article  CAS  PubMed  Google Scholar 

  19. Griesi-Oliveira K, Acab A, Gupta AR, Sunaga DY, Chailangkarn T, Nicol X et al. Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons. Mol Psychiatry 2014 [Epub ahead of print].

  20. Espuny-Camacho I, Michelsen KA, Gall D, Linaro D, Hasche A, Bonnefont J et al. Pyramidal neurons derived from human pluripotent stem cells integrate efficiently into mouse brain circuits in vivo. Neuron 2013; 77: 440–456.

    Article  CAS  PubMed  Google Scholar 

  21. Ohashi Y, Tsubota T, Sato A, Koyano KW, Tamura K, Miyashita Y . A bicistronic lentiviral vector-based method for differential transsynaptic tracing of neural circuits. Mol Cell Neurosci 2011; 46: 136–147.

    Article  CAS  PubMed  Google Scholar 

  22. Damak S, Mosinger B, Margolskee RF . Transsynaptic transport of wheat germ agglutinin expressed in a subset of type II taste cells of transgenic mice. BMC Neurosci 2008; 9: 96.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Harris KM, Jensen FE, Tsao B . Three-dimensional structure of dendritic spines and synapses in rat hippocampus (CA1) at postnatal day 15 and adult ages: implications for the maturation of synaptic physiology and long-term potentiation. J Neurosci 1992; 12: 2685–2705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bauters M, Van Esch H, Friez MJ, Boespflug-Tanguy O, Zenker M, Vianna-Morgante AM et al. Nonrecurrent MECP2 duplications mediated by genomic architecture-driven DNA breaks and break-induced replication repair. Genome Res 2008; 18: 847–858.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kundakovic M, Chen Y, Guidotti A, Grayson DR . The reelin and GAD67 promoters are activated by epigenetic drugs that facilitate the disruption of local repressor complexes. Mol Pharmacol 2009; 75: 342–354.

    Article  CAS  PubMed  Google Scholar 

  26. Spira ME, Hai A . Multi-electrode array technologies for neuroscience and cardiology. Nat Nanotechnol 2013; 8: 83–94.

    Article  CAS  PubMed  Google Scholar 

  27. Chao HT, Zoghbi HY, Rosenmund C . MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron 2007; 56: 58–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jugloff DG, Jung BP, Purushotham D, Logan R, Eubanks JH . Increased dendritic complexity and axonal length in cultured mouse cortical neurons overexpressing methyl-CpG-binding protein MeCP2. Neurobiol Dis 2005; 19: 18–27.

    Article  CAS  PubMed  Google Scholar 

  29. Zhou Z, Hong EJ, Cohen S, Zhao WN, Ho HY, Schmidt L et al. Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron 2006; 52: 255–269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sala C, Segal M . Dendritic spines: the locus of structural and functional plasticity. Physiol Rev 2014; 94: 141–188.

    Article  CAS  PubMed  Google Scholar 

  31. Cubelos B, Sebastián-Serrano A, Beccari L, Calcagnotto ME, Cisneros E, Kim S et al. Cux1 and Cux2 regulate dendritic branching, spine morphology, and synapses of the upper layer neurons of the cortex. Neuron 2010; 66: 523–535.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Grueber WB, Jan LY, Jan YN . Different levels of the homeodomain protein cut regulate distinct dendrite branching patterns of Drosophila multidendritic neurons. Cell 2003; 112: 805–818.

    Article  CAS  PubMed  Google Scholar 

  33. Li Y, Wang H, Muffat J, Cheng AW, Orlando DA, Lovén J et al. Global transcriptional and translational repression in human-embryonic-stem-cell-derived Rett syndrome neurons. Cell Stem Cell 2013; 13: 446–458.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Wainger BJ, Kiskinis E, Mellin C, Wiskow O, Han SS, Sandoe J et al. Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep 2014; 7: 1–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Odawara A, Saitoh Y, Alhebshi AH, Gotoh M, Suzuki I . Long-term electrophysiological activity and pharmacological response of a human induced pluripotent stem cell-derived neuron and astrocyte co-culture. Biochem Biophys Res Commun 2014; 443: 1176–1181.

    Article  CAS  PubMed  Google Scholar 

  36. Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 1998; 393: 386–389.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the California Institute for Regenerative Medicine (CIRM) TR2-01814 and TR4-06747, the National Institutes of Health through the NIH Director’s New Innovator Award Program (1-DP2-OD006495-01), R01MH094753, the International Rett Syndrome Foundation (IRSF) and a NARSAD Independent Investigator Grant to ARM. Also supported in part by NINDS grants R01 NS058529 (JRL) and K08 NS062711 (MBR), the Fonds voor Wetenschappelijk Onderzoek (FWO) Vlaanderen (G.0767.13) (HVE) (G.084111N10 to CB) and Fondation Jérôme Lejeune, France (CB, SN, HVE). HVE is a senior clinical investigator of the FWO Vlaanderen. EP has been supported by an FWO aspirant fellowship and by a Methusalem grant (KU Leuven and Flanders government). LBT and BHSA were supported by a fellowship from UNIFESP/EPM-Brazil. We are grateful to Professor Nadif-Kasri for sharing a control iPSC cell line and to the patients and their families who participated in this study.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to H Van Esch or A R Muotri.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nageshappa, S., Carromeu, C., Trujillo, C. et al. Altered neuronal network and rescue in a human MECP2 duplication model. Mol Psychiatry 21, 178–188 (2016). https://doi.org/10.1038/mp.2015.128

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2015.128

This article is cited by

Search

Quick links