Altered neuronal network and rescue in a human MECP2 duplication model

S. Nageshappa, C. Carromeu, C. A. Trujillo, P. Mesci, I. Espuny-Camacho, E. Pasciuto, P. Vanderhaeghen, C. M. Verfaillie, S. Raitano, A. Kumar, C. M.B. Carvalho, C. Bagni, M. B. Ramocki, B. H.S. Araujo, L. B. Torres, J. R. Lupski, H. Van Esch, A. R. Muotri

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)178-188
Number of pages11
JournalMolecular Psychiatry
Volume21
Issue number2
DOIs
Publication statusPublished - 01-02-2016

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Methyl-CpG-Binding Protein 2
Induced Pluripotent Stem Cells
Neurons
Epigenomics
Preclinical Drug Evaluations
Histone Deacetylase Inhibitors
Nervous System Diseases
Electrodes
Parturition
Phenotype
Cell Line
Lubs X-linked mental retardation syndrome
Therapeutics

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Nageshappa, S., Carromeu, C., Trujillo, C. A., Mesci, P., Espuny-Camacho, I., Pasciuto, E., ... Muotri, A. R. (2016). Altered neuronal network and rescue in a human MECP2 duplication model. Molecular Psychiatry, 21(2), 178-188. https://doi.org/10.1038/mp.2015.128
Nageshappa, S. ; Carromeu, C. ; Trujillo, C. A. ; Mesci, P. ; Espuny-Camacho, I. ; Pasciuto, E. ; Vanderhaeghen, P. ; Verfaillie, C. M. ; Raitano, S. ; Kumar, A. ; Carvalho, C. M.B. ; Bagni, C. ; Ramocki, M. B. ; Araujo, B. H.S. ; Torres, L. B. ; Lupski, J. R. ; Van Esch, H. ; Muotri, A. R. / Altered neuronal network and rescue in a human MECP2 duplication model. In: Molecular Psychiatry. 2016 ; Vol. 21, No. 2. pp. 178-188.
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Nageshappa, S, Carromeu, C, Trujillo, CA, Mesci, P, Espuny-Camacho, I, Pasciuto, E, Vanderhaeghen, P, Verfaillie, CM, Raitano, S, Kumar, A, Carvalho, CMB, Bagni, C, Ramocki, MB, Araujo, BHS, Torres, LB, Lupski, JR, Van Esch, H & Muotri, AR 2016, 'Altered neuronal network and rescue in a human MECP2 duplication model', Molecular Psychiatry, vol. 21, no. 2, pp. 178-188. https://doi.org/10.1038/mp.2015.128

Altered neuronal network and rescue in a human MECP2 duplication model. / Nageshappa, S.; Carromeu, C.; Trujillo, C. A.; Mesci, P.; Espuny-Camacho, I.; Pasciuto, E.; Vanderhaeghen, P.; Verfaillie, C. M.; Raitano, S.; Kumar, A.; Carvalho, C. M.B.; Bagni, C.; Ramocki, M. B.; Araujo, B. H.S.; Torres, L. B.; Lupski, J. R.; Van Esch, H.; Muotri, A. R.

In: Molecular Psychiatry, Vol. 21, No. 2, 01.02.2016, p. 178-188.

Research output: Contribution to journalArticle

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T1 - Altered neuronal network and rescue in a human MECP2 duplication model

AU - Nageshappa, S.

AU - Carromeu, C.

AU - Trujillo, C. A.

AU - Mesci, P.

AU - Espuny-Camacho, I.

AU - Pasciuto, E.

AU - Vanderhaeghen, P.

AU - Verfaillie, C. M.

AU - Raitano, S.

AU - Kumar, A.

AU - Carvalho, C. M.B.

AU - Bagni, C.

AU - Ramocki, M. B.

AU - Araujo, B. H.S.

AU - Torres, L. B.

AU - Lupski, J. R.

AU - Van Esch, H.

AU - Muotri, A. R.

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Nageshappa S, Carromeu C, Trujillo CA, Mesci P, Espuny-Camacho I, Pasciuto E et al. Altered neuronal network and rescue in a human MECP2 duplication model. Molecular Psychiatry. 2016 Feb 1;21(2):178-188. https://doi.org/10.1038/mp.2015.128