Scaramuzza L, De Rocco G, Desiato G, Cobolli Gigli C, Chiacchiaretta M, Mirabella F, Pozzi D, De Simone M, Conforti P, Pagani M, Benfenati F, Cesca F, Bedogni F, and Landsberger N.
EMBO Molecular Medicine, 2021.
Rett syndrome is a severe neurodevelopmental disorder usually caused by an X-linked MECP2 gene mutation, with symptoms such as growth, motor, and communication loss typically appearing at 6-18 months in humans. Some research suggests that MeCP2 deficiency alters early brain development before symptoms arise and disrupts the feed-forward cycle driving neural network maturity, but this relationship is unclear. In this study, researchers used neurons differentiated from cortical neuroprecursors (NPCs) and Mecp2 null animal models to explore the effects of MeCP2 deficiency and investigate if enhancing neuronal activity with ampakine CX546 during early maturation prevents the onset of molecular and cellular phenotypes observed in Rett syndrome.
To explore neuronal activity in vitro, the scientists used Axion’s noninvasive Maestro multielectrode array (MEA) platform. Results from MEA and other in vitro testing demonstrated that MeCP2 reduces the ability of neurons to respond to stimuli and changes morphology and transcription, while enhancing excitability rescues transcription of several genes, neuronal morphology, and responsiveness to stimuli; in vivo results from Mecp2 null mice confirmed the positive impacts of CX546 administration. Overall, the authors support a reevaluation of the pre-symptomatic phase of Rett syndrome and suggest that additional research may lead to the discovery of novel therapeutic targets for the disorder.
