Maturation Delay of Human GABAergic Neurogenesis in Fragile X Syndrome Pluripotent Stem Cells

Authors: Zhang A, Sokolova I, Domissy A, Davis J, Rao L, Hana Utami K, Wang Y, Hagerman RJ, Pouladi MA, Sanna P, Boland MJ, Loring JF.

Stem Cells Translational Medicine, 2022.


Scientists use Axion’s Maestro MEA platform to explore the pathogenesis of fragile X syndrome and identify new avenues of therapeutic discovery. 

Fragile X syndrome (FXS)—an inherited disorder caused by a mutation in the FMR1 gene—is characterized by mild to moderate intellectual disability, autism spectrum disorder, attention-deficit/hyperactivity disorder, seizures, and other health concerns. Previous research has focused mainly on the role of excitatory neurons in FXS, but more recent evidence suggests that GABAergic inhibitory networks are also important in FXS pathogenesis. In this study, scientists developed a protocol to generate multiple GABAergic neuronal subtypes using FXS-affected human induced pluripotent stem cells (hiPSCs) and used a multiplatform approach to examine the underlying mechanisms of the disorder.  

To examine neuronal activity differences in FXS-derived inhibitory neurons and controls over time in vitro, the researchers used Axion’s label-free Maestro multielectrode array (MEA) platform and demonstrated that “FXS neuronal networks showed higher activity during maturation, suggesting a delay in the developmental switch in GABA response from excitatory to inhibitory function.” These findings, taken together with other results, suggest that loss of the FMRP protein in people with FXS prolongs the proliferative stage of progenitors, resulting in a greater number of immature neurons in later stages of neurogenesis and impaired excitatory-inhibitory circuit development. The authors propose that these findings may open the door to novel therapeutics for FXS in the future.