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

Autor: Scaramuzza L; Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy., De Rocco G; Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.; Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy., Desiato G; IRCCS Humanitas Research Hospital, Milan, Italy.; CNR Institute of Neuroscience, Milan, Italy., Cobolli Gigli C; Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy., Chiacchiaretta M; Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genova, Italy., Mirabella F; IRCCS Humanitas Research Hospital, Milan, Italy.; Department of Biomedical Sciences, Humanitas University, Milan, Italy., Pozzi D; IRCCS Humanitas Research Hospital, Milan, Italy.; Department of Biomedical Sciences, Humanitas University, Milan, Italy., De Simone M; Istituto Nazionale Genetica Molecolare 'Romeo ed Enrica Invernizzi', Milan, Italy., Conforti P; Istituto Nazionale Genetica Molecolare 'Romeo ed Enrica Invernizzi', Milan, Italy.; Department of Biosciences, University of Milan, Milan, Italy., Pagani M; Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.; Istituto Nazionale Genetica Molecolare 'Romeo ed Enrica Invernizzi', Milan, Italy., Benfenati F; Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genova, Italy.; IRCCS Ospedale Policlinico San Martino, Genova, Italy., Cesca F; Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genova, Italy.; Department of Life Sciences, University of Trieste, Trieste, Italy., Bedogni F; Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy., Landsberger N; Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.; Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
Jazyk: angličtina
Zdroj: EMBO molecular medicine [EMBO Mol Med] 2021 Apr 09; Vol. 13 (4), pp. e12433. Date of Electronic Publication: 2021 Mar 05.
DOI: 10.15252/emmm.202012433
Abstrakt: 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.
(© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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