The enhancement of activity rescues the establishment of Mecp2 null neuronal phenotypes.

Linda Scaramuzza,Fabrizia Cesca,Massimiliano Pagani,Nicoletta Landsberger,Marco De Simone,Giuseppina De Rocco,Davide Pozzi,Clementina Cobolli Gigli,Fabio Benfenati,Genni Desiato,Paola Conforti,Filippo Mirabella,Francesco Bedogni,Martina Chiacchiaretta

doi:10.15252/emmm.202012433

Abstract

MECP2 mutations cause Rett syndrome (RTT), a severe and progressive neurodevelopmental disorder mainly affecting females. Although RTT patients exhibit delayed onset of symptoms, several evidences demonstrate that MeCP2 deficiency alters early development of the brain. Indeed, during early maturation, Mecp2 null cortical neurons display widespread transcriptional changes, reduced activity, and defective morphology. It has been proposed that during brain development these elements are linked in a feed‐forward cycle where neuronal activity drives transcriptional and morphological changes that further increase network maturity. We hypothesized that the enhancement of neuronal activity during early maturation might prevent the onset of RTT‐typical molecular and cellular phenotypes. Accordingly, we show that the enhancement of excitability, obtained by adding to neuronal cultures Ampakine CX546, rescues transcription of several genes, neuronal morphology, and responsiveness to stimuli. Greater effects are achieved in response to earlier treatments. In vivo, short and early administration of CX546 to Mecp2 null mice prolongs lifespan, delays the disease progression, and rescues motor abilities and spatial memory, thus confirming the value for RTT of an early restoration of neuronal activity.

Highlights

Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene are associated with a number of neurological conditions among which the most frequent is Rett syndrome (RTT; Amir et al, 1999)
Recent preclinical and clinical studies demonstrate that besides the importance of Mecp2 in maintaining neuronal structures (Guy et al, 2007; McGraw et al, 2011; Cheval et al, 2012; Nguyen et al, 2012), its deficiency strongly affects embryonic and early postnatal development (Ip et al, 2018), long before the full outbreak of symptoms (Cosentino et al, 2019; Zhang et al, 2019). We contributed to this novel perspective by demonstrating that Mecp2 null neurons display aberrant transcriptional profiles, reduced responsiveness to stimuli and poor morphology already during early corticogenesis (Bedogni et al, 2016; Cobolli Gigli et al, 2018)
Based on the hypothesis of a crucial role played by neuronal activity in the establishment of mature neuronal networks (Spitzer, 2006), we investigated whether the reduced responsiveness of Mecp2 null neurons participates to their poor transcriptional and morphological features that would further contribute to the overall immaturity of the networks

Summary

Introduction

Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene are associated with a number of neurological conditions among which the most frequent is Rett syndrome (RTT; Amir et al, 1999). RTT is the most common cause of severe intellectual disability in females, as it affects one female every 10,000 born alive (Chahrour & Zoghbi, 2007). Given the high levels of MeCP2 in the brain, the neurological features of RTT are by far the most thoroughly described. Small brain size and reduced weight, thin corpus callosum, and diminished cortical thickness are typical of the pathology (Armstrong et al, 2001; Carter et al, 2008; Belichenko et al, 2009). Diversely from most RTT girls, they feature significantly reduced life span. Defective neuronal features have been reported in the RTT

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