Altered neuronal network and rescue in a human MECP2 duplication model.

TitleAltered neuronal network and rescue in a human MECP2 duplication model.
Publication TypeJournal Article
Year of Publication2016
AuthorsNageshappa, 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
JournalMol Psychiatry
Date Published2016 Feb
KeywordsCell Differentiation, Dendrites, Gene Dosage, Gene Duplication, Genetic Association Studies, Humans, Induced Pluripotent Stem Cells, Male, Methyl-CpG-Binding Protein 2, Nerve Net, Neurogenesis, Neurons

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.

Alternate JournalMol Psychiatry
PubMed ID26347316
PubMed Central IDPMC4720528
Grant List1-DP2-OD006495-01 / OD / NIH HHS / United States
DP2 OD006495 / OD / NIH HHS / United States
R01NS058529 / NS / NINDS NIH HHS / United States
K08 NS062711 / NS / NINDS NIH HHS / United States
R01 MH094753 / MH / NIMH NIH HHS / United States
T32 NS043124 / NS / NINDS NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
R01MH094753 / MH / NIMH NIH HHS / United States

Similar Publications