Journal article
Wide spectrum of neuronal and network phenotypes in human stem cell-derived excitatory neurons with Rett syndrome-associated MECP2 mutations
Translational psychiatry, v 12(1), 450
18 Oct 2022
PMID: 36253345
Abstract
Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by heterozygous loss-of-function mutations in the X-linked gene MECP2 that is a global transcriptional regulator. Mutations in the methyl-CpG binding domain (MBD) of MECP2 disrupt its interaction with methylated DNA. Here, we investigate the effect of a novel MECP2 L124W missense mutation in the MBD of an atypical RTT patient with preserved speech in comparison to severe MECP2 null mutations. L124W protein had a limited ability to disrupt heterochromatic chromocenters due to decreased binding dynamics. We isolated two pairs of isogenic WT and L124W induced pluripotent stem cells. L124W induced excitatory neurons expressed stable protein, exhibited increased input resistance and decreased voltage-gated Na+ and K+ currents, and their neuronal dysmorphology was limited to decreased dendritic complexity. Three isogenic pairs of MECP2 null neurons had the expected more extreme morphological and electrophysiological phenotypes. We examined development and maturation of L124W and MECP2 null excitatory neural network activity using micro-electrode arrays. Relative to isogenic controls, L124W neurons had an increase in synchronous network burst frequency, in contrast to MECP2 null neurons that suffered a significant decrease in synchronous network burst frequency and a transient extension of network burst duration. A biologically motivated computational neural network model shows the observed changes in network dynamics are explained by changes in intrinsic Na+ and K+ currents in individual neurons. Our multilevel results demonstrate that RTT excitatory neurons show a wide spectrum of morphological, electrophysiological and circuitry phenotypes that are dependent on the severity of the MECP2 mutation.
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- Title
- Wide spectrum of neuronal and network phenotypes in human stem cell-derived excitatory neurons with Rett syndrome-associated MECP2 mutations
- Creators
- Rebecca S. F. Mok - University of TorontoWenbo Zhang - Hosp Sick Children, Neurosci & Mental Hlth Program, Toronto, ON M5G 0A4, CanadaTaimoor Sheikh - Drexel University, Pathology (and Laboratory Medicine)Kartik Pradeepan - Western UniversityIsabella R. Fernandes - Rady Children's Hospital-San DiegoLeah C. DeJong - University of TorontoGabriel Benigno - Western UniversityMatthew R. Hildebrandt - Hospital for Sick ChildrenMarat Mufteev - Hospital for Sick ChildrenDeivid C. Rodrigues - Hospital for Sick ChildrenWei Wei - Hospital for Sick ChildrenAlina Piekna - Hospital for Sick ChildrenJiajie Liu - Hospital for Sick ChildrenAlysson R. Muotri - Rady Children's Hospital-San DiegoJohn B. Vincent - University of TorontoLyle Muller - Western UniversityJulio Martinez-Trujillo - Western UniversityMichael W. Salter - Hospital for Sick ChildrenJames Ellis - Hospital for Sick Children
- Publication Details
- Translational psychiatry, v 12(1), 450
- Publisher
- Springer Nature
- Number of pages
- 16
- Grant note
- BrainsCAN at Western University through the Canada First Research Excellence Fund (CFREF) NSERC Postgraduate Scholarship-Doctoral (PGS-D) Scholarship McLaughlin Centre Accelerator grant Beta Sigma Phi International Endowment Fund FDN-154336 / CIHR foundation grant; Canadian Institutes of Health Research (CIHR) Ontario Rett Syndrome Association Ontario Brain Institute MOP-133423 / CIHR; Canadian Institutes of Health Research (CIHR) Col Harland Sanders Rett Syndrome Research Fund at the University of Toronto John Evans Leadership Fund
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pathology (and Laboratory Medicine)
- Web of Science ID
- WOS:000869258800001
- Scopus ID
- 2-s2.0-85140002677
- Other Identifier
- 991022093054504721