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Página principal > Artículos > Artículos publicados > Endogenous Syngap1 Alpha Splice Forms Promote Cognitive Function and Seizure Protection |
Fecha: | 2022 |
Resumen: | Loss-of-function variants in SYNGAP1 cause a developmental encephalopathy defined by cognitive impairment, autistic features, and epilepsy. SYNGAP1 splicing leads to expression of distinct functional protein isoforms. Splicing imparts multiple cellular functions of SynGAP proteins through coding of distinct C-terminal motifs. However, it remains unknown how these different splice sequences function in vivo to regulate neuronal function and behavior. Reduced expression of SynGAP-α1/2 C-terminal splice variants in mice caused severe phenotypes, including reduced survival, impaired learning, and reduced seizure latency. In contrast, upregulation of α1/2 expression improved learning and increased seizure latency. Mice expressing α1-specific mutations, which disrupted SynGAP cellular functions without altering protein expression, promoted seizure, disrupted synapse plasticity, and impaired learning. These findings demonstrate that endogenous SynGAP isoforms with α1/2 spliced sequences promote cognitive function and impart seizure protection. Regulation of SynGAP-α expression or function may be a viable therapeutic strategy to broadly improve cognitive function and mitigate seizure. |
Ayudas: | Ministerio de Ciencia, Innovación y Universidades IEDI-2017-00822 Ministerio de Ciencia, Innovación y Universidades RTI2018-097037-B-I00 Ministerio de Economía y Competitividad BES-2013-063720 Agència de Gestió d'Ajuts Universitaris i de Recerca SGR14-297 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017SGR1776 European Commission EU/AC17/00005 Agencia Estatal de Investigación RYC-2011-08391 Instituto de Salud Carlos III AES2017 Ministerio de Economía y Competitividad IEDI-2017-00822 |
Nota: | Altres ajuts: NIH grants from the National Institute of Mental Health (MH096847, MH108408, MH115005, MH113949, MH105400); National Institute for Neurological Disorders and Stroke (NS064079); Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD089491); National Institute for Drug Abuse (DA034116, DA036376); Autism Speaks Weatherstone Pre-Doctoral fellowship (10646); Training fellowship from the Leon and Friends Charitable Foundation. |
Derechos: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. |
Lengua: | Anglès |
Documento: | Article de revisió ; recerca ; Versió publicada |
Publicado en: | eLife, Vol. 11 (april 2022) , p. e75707, ISSN 2050-084X |
34 p, 3.4 MB |