Altered neuronal network and rescue in a human MECP2 duplication model
Open accessAbstract
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.
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Cellular models of MECP2 gain of function exhibit opposite effects of increased synapses and dendrites.
“Importantly, cellular models of the reciprocal MECP2 gain of function (MECP2 duplication syndrome, (Lugtenberg et al., 2009) exhibit the opposite effects of increased synapses and dendrites (Nageshappa et al., 2016).”
From Getting to the cores of autism (2019) · cites this paper as Nageshappa et al., 2016
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- Authors
- 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.
- Affiliations
- KU Leuven (BE)
- University of California San Diego (US)
- Université Libre de Bruxelles (BE)
- Leuven Stem Cell Institute (BE)
- Manipal Academy of Higher Education (IN)
- Baylor College of Medicine (US)
- University of Rome Tor Vergata (IT)
- Corresponding author
- Muotri, A R
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2015-09-08
- Volume
- 21
- Issue
- 2
- Pages
- 178-188
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC4720528
- OpenAlex
- W1777711993
- Cited by
- 117
- References
- 36
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 10 · 2023: 2 · 2022: 14 · 2021: 9 · 2020: 20 · 2019: 12 · 2018: 13 · 2017: 12 · 2016: 11 · 2015: 1
- FWCI
- 8.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Americanae (AECID Library) (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ORBi (University of Liège) (submittedVersion, other-oa)
- Arca - Repositório Institucional da Fiocruz (submittedVersion, other-oa)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Lirias (submittedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- Funders
- California Institute for Regenerative Medicine (TR4-06747, TR2-01814)
- International Rett Syndrome Foundation
- National Alliance for Research on Schizophrenia and Depression
- Fonds Wetenschappelijk Onderzoek
- KU Leuven
- Vlaamse regering
- National Institutes of Health (TR4-06747, 1dp2od006495-01)
- National Institute of Mental Health (R01MH094753)
- National Institute of Neurological Disorders and Stroke (R01NS058529, T32NS043124, K08NS062711)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- MECP2 duplication syndrome, induced pluripotent stem cells, cortical neurons, neuronal network synchronization, synaptogenesis, dendritic complexity, epigenetic therapy, histone deacetylase inhibitors, drug screening, neurodevelopmental disorders, iPSC-derived neurons
- MeSH terms
- Cell Differentiation, Dendrites, Humans, Male, Nerve Net, Neurons, Gene Dosage, Gene Duplication, Methyl-CpG-Binding Protein 2, Neurogenesis, Genetic Association Studies, Induced Pluripotent Stem Cells
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