Pharmacological reversal of synaptic and network pathology in human MECP2 ‐KO neurons and cortical organoids

Abstract

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.

Brain Organoids: Studying Human Brain Development and Diseases in a Dish

“…Attracted by the unique advantages of brain organoids, more and more researchers devoted themselves into this field and established many more disease models for the investigation of disease mechanisms. For example, most recently, MECP2 knockout neurospheres and cortical organoids were generated for modeling Rett syndrome [144]; Down syndrome cerebral organoid models were established from patient-derived iPSCs [145]; and iPSCderived brain organoids infected by a "clinical-like" human cytomegalovirus (HCMV) strain were utilized for studying HCMV-induced microcephaly [146]. Furthermore, such disease-modeling organoids also provide a platform for drug screening [88,89] and act as a subject in the investigation of potential organoid transplantation therapy for neurological disorders [147][148][149].…”

Music-Based Intervention Ameliorates Mecp2-Loss-Mediated Sociability Repression in Mice through the Prefrontal Cortex FNDC5/BDNF Pathway

“…We successfully established a music-based intervention model in RTT in vivo; however, the analysis of FNDC5/BDNF signaling pathways hinted at the complex nature of biological activity in brain tissue that the intervention may influence. Engibeerin cortical organoids from human-induced pluripotent stem cells (iPSCs), showing neurite undergrowth, neurite coalescence, and soma size of interneurons, have recently been used as an in vitro RTT model [51,52]. The biological response or the roles of FNDC5/BNDF pathways in an in vitro humanized RTT model upon different music-based interventions, such as magnitude and frequency (Hz) of music, warrant further investigations in the future.…”

The Age of Brain Organoids: Tailoring Cell Identity and Functionality for Normal Brain Development and Disease Modeling

“…Increased proliferation in detriment of neuronal generation was suggested as the cause of delayed development observed in 2D neuronal cultures (Mellios et al, 2018). MEA electrophysiology conducted in MECP2-KO cortical organoids showed decreased population spiking compared with the controls, which could be rescued with treatment with selected compounds from a drug screening (Trujillo et al, 2021). Region-specific organoids with cortical specialization and medial ganglionic eminence (MGE), a critical ventral brain domain producing cortical interneurons and related lineages (Xiang et al, 2017), were generated from hESC with MeCP2 mutation.…”