The enhancement of activity rescues the establishment of Mecp2 null neuronal phenotypes
| العنوان: | The enhancement of activity rescues the establishment of Mecp2 null neuronal phenotypes |
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| المؤلفون: | Massimiliano Pagani, Davide Pozzi, Linda Scaramuzza, M. De Simone, D. Genni, Filippo Mirabella, Fabio Benfenati, Fabrizia Cesca, Nicoletta Landsberger, G. De Rocco, C. G. Clementina, Martina Chiacchiaretta, Paola Conforti, Francesco Bedogni |
| المساهمون: | 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., Landsberger, N. |
| المصدر: | EMBO Molecular Medicine EMBO Molecular Medicine, Vol 13, Iss 4, Pp n/a-n/a (2021) |
| بيانات النشر: | John Wiley and Sons Inc., 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Ampakine, Medicine (General), congenital, hereditary, and neonatal diseases and abnormalities, Offspring, medicine.drug_class, Methyl-CpG-Binding Protein 2, Rett syndrome, Biology, QH426-470, Article, neuronal activity, MECP2, 03 medical and health sciences, Mice, 0302 clinical medicine, Neurodevelopmental disorder, R5-920, neuronal maturation, In vivo, Transcription (biology), medicine, Genetics, Premovement neuronal activity, Animals, Humans, Gene, Mecp2, 030304 developmental biology, Neurons, 0303 health sciences, Brain, Articles, medicine.disease, Phenotype, 3. Good health, 030104 developmental biology, nervous system, Molecular Medicine, Female, Genetics, Gene Therapy & Genetic Disease, Neuroscience, 030217 neurology & neurosurgery |
| الوصف: | 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. 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. |
| اللغة: | English |
| تدمد: | 1757-4684 1757-4676 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b09a6f93f9505c33ebd8d3fe0f3407bcTest http://europepmc.org/articles/PMC8033520Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b09a6f93f9505c33ebd8d3fe0f3407bc |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17574684 17574676 |
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