Open AccessPharmacological reversal of synaptic and network pathology in human MECP2 ‐KO neurons and cortical organoids
Author(s) -
Trujillo Cleber A,
Adams Jason W,
Negraes Priscilla D,
Carromeu Cassiano,
Tejwani Leon,
Acab Allan,
Tsuda Ben,
Thomas Charles A,
Sodhi Neha,
Fichter Katherine M,
Romero Sarah,
Zanella Fabian,
Sejnowski Terrence J,
Ulrich Henning,
Muotri Alysson R
Publication year - 2020
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202012523
Subject(s) - medicine , medical school , gerontology , library science , medical education , computer science
Duplication or deficiency of the X‐linked MECP2 gene reliably produces profound neurodevelopmental impairment. MECP2 mutations are almost universally responsible for Rett syndrome (RTT), and particular mutations and cellular mosaicism of MECP2 may underlie the spectrum of RTT symptomatic severity. No clinically approved treatments for RTT are currently available, but human pluripotent stem cell technology offers a platform to identify neuropathology and test candidate therapeutics. Using a strategic series of increasingly complex human stem cell‐derived technologies, including human neurons, MECP2 ‐mosaic neurospheres to model RTT female brain mosaicism, and cortical organoids, we identified synaptic dysregulation downstream from knockout of MECP2 and screened select pharmacological compounds for their ability to treat this dysfunction. Two lead compounds, Nefiracetam and PHA 543613, specifically reversed MECP2‐ knockout cytologic neuropathology. The capacity of these compounds to reverse neuropathologic phenotypes and networks in human models supports clinical studies for neurodevelopmental disorders in which MeCP2 deficiency is the predominant etiology.