Wide spectrum of neuronal and network phenotypes in human stem cell-derived excitatory neurons with Rett syndrome-associated<i>MECP2</i>mutations

ABSTRACT Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by heterozygous loss-of-function mutations in the X-linked geneMECP2that 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 ofMECP2L124W missense mutation in the MBD of an atypical RTT patient in comparison to severeMECP2null 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 ofMECP2null neurons had the expected more extreme morphological and electrophysiological phenotypes. We examined development and maturation of L124W andMECP2null excitatory neural network activity using micro-electrode arrays. Relative to isogenic controls, L124W neurons had an increase in synchronous network burst frequency, in contrast toMECP2null neurons that suffered a significant decrease in synchronous network burst frequency and a transient extension of network burst duration. We capture these findings in a computational neural network model that shows the observed changes in network dynamics are best explained by changes in intrinsic adaptation 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 theMECP2mutation..

Medienart:

Preprint

Erscheinungsjahr:

2023

Erschienen:

2023

Enthalten in:

bioRxiv.org - (2023) vom: 04. Okt. Zur Gesamtaufnahme - year:2023

Sprache:

Englisch

Beteiligte Personen:

Mok, Rebecca SF [VerfasserIn]
Zhang, Wenbo [VerfasserIn]
Sheikh, Taimoor I [VerfasserIn]
Pradeepan, Kartik [VerfasserIn]
Fernandes, Isabella R [VerfasserIn]
DeJong, Leah C [VerfasserIn]
Benigno, Gabriel [VerfasserIn]
Hildebrandt, Matthew R [VerfasserIn]
Mufteev, Marat [VerfasserIn]
Rodrigues, Deivid C [VerfasserIn]
Wei, Wei [VerfasserIn]
Piekna, Alina [VerfasserIn]
Liu, Jiajie [VerfasserIn]
Muotri, Alysson R [VerfasserIn]
Vincent, John B [VerfasserIn]
Muller, Lyle [VerfasserIn]
Martinez-Trujillo, Julio [VerfasserIn]
Salter, Michael W [VerfasserIn]
Ellis, James [VerfasserIn]

Links:

Volltext [kostenfrei]

Themen:

570
Biology

doi:

10.1101/2020.07.12.189621

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

XBI018340156