Please use this identifier to cite or link to this item: http://hdl.handle.net/10316/100110
Title: Aberrant hippocampal transmission and behavior in mice with a stargazin mutation linked to intellectual disability
Authors: 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. 
Issue Date: 7-Mar-2022
Publisher: Springer Nature
Project: UID/NEU/04539/2013 
UIDB/04539/2020 
POCI-01-0145-FEDER-28541 
POCI-01-0145- FEDER-016682 
PTDC/QUI-OUT/32243/2017 
CPCA/A0/7302/2020 
CENTRO-01-0145-FEDER-000008:BrainHealth 2020 
info:eu-repo/grantAgreement/FCT/SFRH/SFRH/BD/51962/2012/PT 
info:eu-repo/grantAgreement/FCT/POR_CENTRO/SFRH/BD/144881/2019/PT/Cerebellar dysfunction in neuropsychiatric disorders: insights from human mutations in Stargazin 
info:eu-repo/grantAgreement/FCT/POR_CENTRO/SFRH/BD/129236/2017/PT/STARGAZIN AS A REGULATOR OF M-CURRENTS IN THE CENTRAL NERVOUS SYSTEM 
info:eu-repo/grantAgreement/FCT/SFRH/SFRH/2FBD/2F51958/2F2012/PT 
info:eu-repo/grantAgreement/FCT/OE/SFRH/BD/145457/2019/PT/A computational approach to the structural and dynamical characterization of the ghrelin receptor function and mechanism 
info:eu-repo/grantAgreement/FCT/FARH/SFRH/BPD/122299/2016/PT/COGNITIVE DISORDERS AS DEFECTS IN SYNAPTIC FUNCTION: INSIGHT FROM HUMAN MUTATIONS IN THE CACNG2 GENE 
info:eu-repo/grantAgreement/FCT/POR_CENTRO/SFRH/BPD/120611/2016/PT/Dissecting the role of metabotropic glutamate receptor sorting proteins in autism spectrum disorders 
Serial title, monograph or event: Molecular Psychiatry
Abstract: 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.
URI: http://hdl.handle.net/10316/100110
ISSN: 1359-4184
1476-5578
DOI: 10.1038/s41380-022-01487-w
Rights: openAccess
Appears in Collections:FCTUC Ciências da Vida - Artigos em Revistas Internacionais
IIIUC - Artigos em Revistas Internacionais
I&D CNC - Artigos em Revistas Internacionais

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