Autor(es):
Caldeira, G. L. ; Inácio, A. ; Beltrão, N. ; Barreto, C. A. V. ; Rodrigues, M. V. ; Rondão, T. ; Macedo, R. ; Gouveia, R. P. ; Edfawy, M. ; Guedes, J. ; Cruz, B. ; Louros, S. R. ; Moreira, I. S. ; Peça, J. ; Carvalho, A. L.
Data: 2022
Identificador Persistente: https://hdl.handle.net/10316/100110
Origem: Estudo Geral - Universidade de Coimbra
Projeto/bolsa:
info:eu-repo/grantAgreement/FCT/SFRH/SFRH/PT;
info:eu-repo/grantAgreement/FCT/POR_CENTRO/SFRH/PT;
info:eu-repo/grantAgreement/FCT/POR_CENTRO/SFRH/PT;
info:eu-repo/grantAgreement/FCT/SFRH/SFRH/PT;
info:eu-repo/grantAgreement/FCT/OE/SFRH/PT;
info:eu-repo/grantAgreement/FCT/FARH/SFRH/PT;
info:eu-repo/grantAgreement/FCT/POR_CENTRO/SFRH/PT;
info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID/PT;
Descrição
Mutations linked to neurodevelopmental disorders, such as intellectual disability (ID), are frequently found in genes that encode for proteins of the excitatory synapse. Transmembrane AMPA receptor regulatory proteins (TARPs) are AMPA receptor auxiliary proteins that regulate crucial aspects of receptor function. Here, we investigate a mutant form of the TARP family member stargazin, described in an ID patient. Molecular dynamics analyses predicted that the ID-associated stargazin variant, V143L, weakens the overall interface of the AMPAR:stargazin complex and impairs the stability of the complex. Knock-in mice harboring the V143L stargazin mutation manifest cognitive and social deficits and hippocampal synaptic transmission defects, resembling phenotypes displayed by ID patients. In the hippocampus of stargazin V143L mice, CA1 neurons show impaired spine maturation, abnormal synaptic transmission and long-term potentiation specifically in basal dendrites, and synaptic ultrastructural alterations. These data suggest a causal role for mutated stargazin in the pathogenesis of ID and unveil a new role for stargazin in the development and function of hippocampal synapses.
This work was supported by a NARSAD Independent Investigator Grant (#23151) and a NARSAD Young Investigator Grant (#20733) from the Brain and Behavior Research Foundation, by a research grant from the Jérôme Lejeune Foundation (#1530), by “la Caixa” Foundation (ID 100010434), and FCT, I.P under the project code LCF/PR/HP20/52300003, by a Marie Curie Integration Grant (618525), by a Bial Foundation Grant (266/2016), by national funds through the Portuguese Science and Technology Foundation (FCT: UID/NEU/04539/2013, UIDB/04539/2020, POCI-01-0145-FEDER-28541, POCI-01-0145-FEDER-016682, PTDC/QUI-OUT/32243/2017 and CPCA/A0/7302/2020), and by the European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme, under project CENTRO-01-0145-FEDER-000008:BrainHealth 2020. GLC, NB, MVR, ME and CAVB were supported by FCT through Ph.D. scholarships SFRH/BD/51962/2012, SFRH/BD/144881/2019, SFRH/BD/129236/2017, SFRH/BD/51958/2012 and SFRH/BD/145457/2019, respectively. ASI and JG were supported by FCT through Postdoctoral fellowship SFRH/BPD122299/2016 and SFRH/BPD/120611/2016, respectively. RPG and RM received support from FCT/DGES, under the program “Verão com Ciência”.
