Early differential impact of MeCP2 mutations on functional networks in Rett syndrome patient-derived human cerebral organoids.

Autor: Osaki T; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Delepine C; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Osako Y; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Kranz D; Boston Children's Hospital, Brookline, MA 02445, USA.; Harvard University, Cambridge, MA 02139, USA., Levin A; Boston Children's Hospital, Brookline, MA 02445, USA., Nelson C; Boston Children's Hospital, Brookline, MA 02445, USA.; Harvard University, Cambridge, MA 02139, USA., Fagiolini M; Boston Children's Hospital, Brookline, MA 02445, USA.; Harvard University, Cambridge, MA 02139, USA., Sur M; Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Jazyk: angličtina
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2024 Aug 10. Date of Electronic Publication: 2024 Aug 10.
DOI: 10.1101/2024.08.10.607464
Abstrakt: Human cerebral organoids derived from induced pluripotent stem cells can recapture early developmental processes and reveal changes involving neurodevelopmental disorders. Mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene are associated with Rett syndrome, and disease severity varies depending on the location and type of mutation. Here, we focused on neuronal activity in Rett syndrome patient-derived organoids, analyzing two types of MeCP2 mutations - a missense mutation (R306C) and a truncating mutation (V247X) - using calcium imaging with three-photon microscopy. Compared to isogenic controls, we found abnormal neuronal activity in Rett organoids and altered network function based on graph theoretic analyses, with V247X mutations impacting functional responses and connectivity more severely than R306C mutations. These changes paralleled EEG data obtained from patients with comparable mutations. Labeling DLX promoter-driven inhibitory neurons demonstrated differences in activity and functional connectivity of inhibitory and excitatory neurons in the two types of mutation. Transcriptomic analyses revealed HDAC2-associated impairment in R306C organoids and decreased GABA A receptor expression in excitatory neurons in V247X organoids. These findings demonstrate mutation-specific mechanisms of vulnerability in Rett syndrome and suggest targeted strategies for their treatment.
Databáze: MEDLINE
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