The enhancement of activity rescues the establishment of Mecp2 null neuronal phenotypes. Issue 4 (5th March 2021)

• Record Type: Journal Article
• Authors: Scaramuzza, Linda; De Rocco, Giuseppina; Desiato, Genni; Cobolli Gigli, Clementina; Chiacchiaretta, Martina; Mirabella, Filippo; Pozzi, Davide; De Simone, Marco; Conforti, Paola; Pagani, Massimiliano; Benfenati, Fabio; Cesca, Fabrizia; Bedogni, Francesco; Landsberger, Nicoletta
• Is Part Of: EMBO molecular medicine. Volume 13:Issue 4(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-03-05
• Subjects: Ampakine -- Mecp2 -- neuronal activity -- neuronal maturation -- Rett syndrome; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.202012433
• Languages: English
• ISSNs: 1757-4676

Abstract

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. Synopsis: Neuronal activity drives transcriptional and morphological changes that ensure maturation. Such mechanism is affected by Mecp2 absence. We show the rescue effects produced by enhancing Mecp2 null neurons activity and propose new therapeutic time windows for the treatment of Rett syndrome. In normal conditions, neuronal activity, transcription and morphology cooperate in a feed forward cycle that ensures proper maturation. This feed forward cycle is disrupted in Rett syndrome neurons, which display functional, transcriptional and morphological defects already during early development. In vitro, enhancement of activity rescues typical phenotypes of the otherwise immature Mecp2 null neurons, with larger effects in response to earlier treatments. Our in vivo data confirm the therapeutic potential of treatments that enhance neuronal activity during early developmental time windows. Abstract : Neuronal activity drives transcriptional and morphological changes that ensure maturation. Such mechanism is affected by Mecp2 absence. We show the rescue effects produced by enhancing Mecp2 null neurons activity and propose new therapeutic time windows for the treatment of Rett syndrome.