Altered neuronal network and rescue in a human MECP2 duplication model

• Published in: Molecular psychiatry Vol. 21; no. 2; pp. 178 - 188
• Main 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2016; Nature Publishing Group
• Subjects: 13/1; 13/100; 13/106; 13/44; 14/63; 38/77; 631/154; 631/378; 631/532; Behavioral Sciences; Biological Psychology; Biology; Care and treatment; Cell Differentiation; Dendrites - metabolism; Disease; Dosage; Drug dosages; Drug screening; Epigenetic inheritance; Epigenetics; Epilepsy; Gene Dosage - physiology; Gene Duplication - genetics; Genetic Association Studies; Genomes; Genotype & phenotype; Health aspects; Histone deacetylase; Humans; Induced Pluripotent Stem Cells; Inhibitory postsynaptic potentials; Male; MeCP2 protein; Medicine; Medicine & Public Health; Methyl-CpG binding protein; Methyl-CpG-Binding Protein 2 - genetics; Methyl-CpG-Binding Protein 2 - physiology; Mutation; Nerve Net - metabolism; Nervous system diseases; Neurodevelopmental disorders; Neurogenesis; Neurological diseases; Neurons; Neurosciences; original-article; Patients; Pediatrics; Pharmacotherapy; Phenotypes; Pluripotency; Protein binding; Proteins; Psychiatry; Risk factors; Stem cells; Synaptogenesis; Synchronization; Belgium; California; La Jolla California; United States > US
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2015.128

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 ( MECP2 dup), carrying different duplication sizes, to study the impact of increased MeCP2 dosage in human neurons. We show that cortical neurons derived from these different MECP2 dup iPSC lines have increased synaptogenesis and dendritic complexity. In addition, using multi-electrodes arrays, we show that neuronal network synchronization was altered in MECP2 dup-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.