Aberrant hippocampal transmission and behavior in mice with a stargazin mutation linked to intellectual disability.

Autor: Caldeira GL; CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.; IIIUC-Institute for Interdisciplinary Research, University of Coimbra, 3030-789, Coimbra, Portugal.; PhD Program in Experimental Biology and Biomedicine (PDBEB), University of Coimbra, Coimbra, Portugal., Inácio AS; CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.; IIIUC-Institute for Interdisciplinary Research, University of Coimbra, 3030-789, Coimbra, Portugal., Beltrão N; CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.; IIIUC-Institute for Interdisciplinary Research, University of Coimbra, 3030-789, Coimbra, Portugal.; PhD Program in Experimental Biology and Biomedicine (PDBEB), University of Coimbra, Coimbra, Portugal., Barreto CAV; CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.; IIIUC-Institute for Interdisciplinary Research, University of Coimbra, 3030-789, Coimbra, Portugal.; PhD Program in Experimental Biology and Biomedicine (PDBEB), University of Coimbra, Coimbra, Portugal., Rodrigues MV; CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.; IIIUC-Institute for Interdisciplinary Research, University of Coimbra, 3030-789, Coimbra, Portugal.; PhD Program in Experimental Biology and Biomedicine (PDBEB), University of Coimbra, Coimbra, Portugal., Rondão T; CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal., Macedo R; CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.; Department of Life Sciences, University of Coimbra, 3000-456, Coimbra, Portugal., Gouveia RP; CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.; Department of Life Sciences, University of Coimbra, 3000-456, Coimbra, Portugal., Edfawy M; CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.; IIIUC-Institute for Interdisciplinary Research, University of Coimbra, 3030-789, Coimbra, Portugal.; PhD Program in Experimental Biology and Biomedicine (PDBEB), University of Coimbra, Coimbra, Portugal.; HEMEX AG, Liestal, Switzerland., Guedes J; CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.; IIIUC-Institute for Interdisciplinary Research, University of Coimbra, 3030-789, Coimbra, Portugal., Cruz B; CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.; Department of Life Sciences, University of Coimbra, 3000-456, Coimbra, Portugal.; Champalimaud Research, Champalimaud Centre for the Unknown, Lisbon, Portugal., Louros SR; CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.; IIIUC-Institute for Interdisciplinary Research, University of Coimbra, 3030-789, Coimbra, Portugal.; Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK., Moreira IS; CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.; Department of Life Sciences, University of Coimbra, 3000-456, Coimbra, Portugal., Peça J; CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.; Department of Life Sciences, University of Coimbra, 3000-456, Coimbra, Portugal., Carvalho AL; CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal. alc@cnc.uc.pt.; Department of Life Sciences, University of Coimbra, 3000-456, Coimbra, Portugal. alc@cnc.uc.pt.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2022 May; Vol. 27 (5), pp. 2457-2469. Date of Electronic Publication: 2022 Mar 07.
DOI: 10.1038/s41380-022-01487-w
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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