The enhancement of activity rescues the establishment of Mecp2 null neuronal phenotypes
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...
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Springer Nature
2021-03-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202012433 |
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| author | Linda Scaramuzza Giuseppina De Rocco Genni Desiato Clementina Cobolli Gigli Martina Chiacchiaretta Filippo Mirabella Davide Pozzi Marco De Simone Paola Conforti Massimiliano Pagani Fabio Benfenati Fabrizia Cesca Francesco Bedogni Nicoletta Landsberger |
| author_facet | Linda Scaramuzza Giuseppina De Rocco Genni Desiato Clementina Cobolli Gigli Martina Chiacchiaretta Filippo Mirabella Davide Pozzi Marco De Simone Paola Conforti Massimiliano Pagani Fabio Benfenati Fabrizia Cesca Francesco Bedogni Nicoletta Landsberger |
| author_sort | Linda Scaramuzza |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-2bd801b819f54039b58d0e6634ff886c |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2021-03-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-2bd801b819f54039b58d0e6634ff886c2025-08-20T03:42:52ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-03-0113411810.15252/emmm.202012433The enhancement of activity rescues the establishment of Mecp2 null neuronal phenotypesLinda Scaramuzza0Giuseppina De Rocco1Genni Desiato2Clementina Cobolli Gigli3Martina Chiacchiaretta4Filippo Mirabella5Davide Pozzi6Marco De Simone7Paola Conforti8Massimiliano Pagani9Fabio Benfenati10Fabrizia Cesca11Francesco Bedogni12Nicoletta Landsberger13Division of Neuroscience, IRCCS San Raffaele Scientific InstituteDivision of Neuroscience, IRCCS San Raffaele Scientific InstituteIRCCS Humanitas Research HospitalDivision of Neuroscience, IRCCS San Raffaele Scientific InstituteCenter for Synaptic Neuroscience and Technology, Istituto Italiano di TecnologiaIRCCS Humanitas Research HospitalIRCCS Humanitas Research HospitalIstituto Nazionale Genetica Molecolare “Romeo ed Enrica Invernizzi”Istituto Nazionale Genetica Molecolare “Romeo ed Enrica Invernizzi”Department of Medical Biotechnology and Translational Medicine, University of MilanCenter for Synaptic Neuroscience and Technology, Istituto Italiano di TecnologiaCenter for Synaptic Neuroscience and Technology, Istituto Italiano di TecnologiaDivision of Neuroscience, IRCCS San Raffaele Scientific InstituteDivision of Neuroscience, IRCCS San Raffaele Scientific InstituteAbstract 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.https://doi.org/10.15252/emmm.202012433AmpakineMecp2neuronal activityneuronal maturationRett syndrome |
| spellingShingle | Linda Scaramuzza Giuseppina De Rocco Genni Desiato Clementina Cobolli Gigli Martina Chiacchiaretta Filippo Mirabella Davide Pozzi Marco De Simone Paola Conforti Massimiliano Pagani Fabio Benfenati Fabrizia Cesca Francesco Bedogni Nicoletta Landsberger The enhancement of activity rescues the establishment of Mecp2 null neuronal phenotypes EMBO Molecular Medicine Ampakine Mecp2 neuronal activity neuronal maturation Rett syndrome |
| title | The enhancement of activity rescues the establishment of Mecp2 null neuronal phenotypes |
| title_full | The enhancement of activity rescues the establishment of Mecp2 null neuronal phenotypes |
| title_fullStr | The enhancement of activity rescues the establishment of Mecp2 null neuronal phenotypes |
| title_full_unstemmed | The enhancement of activity rescues the establishment of Mecp2 null neuronal phenotypes |
| title_short | The enhancement of activity rescues the establishment of Mecp2 null neuronal phenotypes |
| title_sort | enhancement of activity rescues the establishment of mecp2 null neuronal phenotypes |
| topic | Ampakine Mecp2 neuronal activity neuronal maturation Rett syndrome |
| url | https://doi.org/10.15252/emmm.202012433 |
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