Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly

De novo protein synthesis is required for synapse modifications underlying stable memory encoding. Yet neurons are highly compartmentalized cells and how protein synthesis can be regulated at the synapse level is unknown. Here, we characterize neuronal signaling complexes formed by the postsynaptic...

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Autores principales:	María J Conde-Dusman, Partha N Dey, Óscar Elía-Zudaire, Luis G Rabaneda, Carmen García-Lira, Teddy Grand, Victor Briz, Eric R Velasco, Raül Andero, Sergio Niñerola, Angel Barco, Pierre Paoletti, John F Wesseling, Fabrizio Gardoni, Steven J Tavalin, Isabel Perez-Otaño
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	GluN3A NMDA receptor mTOR protein synthesis memory GIT1 Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/77ce7ee1a4f040119c91bf9ba1582051
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spelling	oai:doaj.org-article:77ce7ee1a4f040119c91bf9ba15820512021-11-19T12:20:01ZControl of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly10.7554/eLife.715752050-084Xe71575https://doaj.org/article/77ce7ee1a4f040119c91bf9ba15820512021-11-01T00:00:00Zhttps://elifesciences.org/articles/71575https://doaj.org/toc/2050-084XDe novo protein synthesis is required for synapse modifications underlying stable memory encoding. Yet neurons are highly compartmentalized cells and how protein synthesis can be regulated at the synapse level is unknown. Here, we characterize neuronal signaling complexes formed by the postsynaptic scaffold GIT1, the mechanistic target of rapamycin (mTOR) kinase, and Raptor that couple synaptic stimuli to mTOR-dependent protein synthesis; and identify NMDA receptors containing GluN3A subunits as key negative regulators of GIT1 binding to mTOR. Disruption of GIT1/mTOR complexes by enhancing GluN3A expression or silencing GIT1 inhibits synaptic mTOR activation and restricts the mTOR-dependent translation of specific activity-regulated mRNAs. Conversely, GluN3A removal enables complex formation, potentiates mTOR-dependent protein synthesis, and facilitates the consolidation of associative and spatial memories in mice. The memory enhancement becomes evident with light or spaced training, can be achieved by selectively deleting GluN3A from excitatory neurons during adulthood, and does not compromise other aspects of cognition such as memory flexibility or extinction. Our findings provide mechanistic insight into synaptic translational control and reveal a potentially selective target for cognitive enhancement.María J Conde-DusmanPartha N DeyÓscar Elía-ZudaireLuis G RabanedaCarmen García-LiraTeddy GrandVictor BrizEric R VelascoRaül AnderoSergio NiñerolaAngel BarcoPierre PaolettiJohn F WesselingFabrizio GardoniSteven J TavalinIsabel Perez-OtañoeLife Sciences Publications LtdarticleGluN3ANMDA receptormTORprotein synthesismemoryGIT1MedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	GluN3A NMDA receptor mTOR protein synthesis memory GIT1 Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	GluN3A NMDA receptor mTOR protein synthesis memory GIT1 Medicine R Science Q Biology (General) QH301-705.5 María J Conde-Dusman Partha N Dey Óscar Elía-Zudaire Luis G Rabaneda Carmen García-Lira Teddy Grand Victor Briz Eric R Velasco Raül Andero Sergio Niñerola Angel Barco Pierre Paoletti John F Wesseling Fabrizio Gardoni Steven J Tavalin Isabel Perez-Otaño Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly
description	De novo protein synthesis is required for synapse modifications underlying stable memory encoding. Yet neurons are highly compartmentalized cells and how protein synthesis can be regulated at the synapse level is unknown. Here, we characterize neuronal signaling complexes formed by the postsynaptic scaffold GIT1, the mechanistic target of rapamycin (mTOR) kinase, and Raptor that couple synaptic stimuli to mTOR-dependent protein synthesis; and identify NMDA receptors containing GluN3A subunits as key negative regulators of GIT1 binding to mTOR. Disruption of GIT1/mTOR complexes by enhancing GluN3A expression or silencing GIT1 inhibits synaptic mTOR activation and restricts the mTOR-dependent translation of specific activity-regulated mRNAs. Conversely, GluN3A removal enables complex formation, potentiates mTOR-dependent protein synthesis, and facilitates the consolidation of associative and spatial memories in mice. The memory enhancement becomes evident with light or spaced training, can be achieved by selectively deleting GluN3A from excitatory neurons during adulthood, and does not compromise other aspects of cognition such as memory flexibility or extinction. Our findings provide mechanistic insight into synaptic translational control and reveal a potentially selective target for cognitive enhancement.
format	article
author	María J Conde-Dusman Partha N Dey Óscar Elía-Zudaire Luis G Rabaneda Carmen García-Lira Teddy Grand Victor Briz Eric R Velasco Raül Andero Sergio Niñerola Angel Barco Pierre Paoletti John F Wesseling Fabrizio Gardoni Steven J Tavalin Isabel Perez-Otaño
author_facet	María J Conde-Dusman Partha N Dey Óscar Elía-Zudaire Luis G Rabaneda Carmen García-Lira Teddy Grand Victor Briz Eric R Velasco Raül Andero Sergio Niñerola Angel Barco Pierre Paoletti John F Wesseling Fabrizio Gardoni Steven J Tavalin Isabel Perez-Otaño
author_sort	María J Conde-Dusman
title	Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly
title_short	Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly
title_full	Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly
title_fullStr	Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly
title_full_unstemmed	Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly
title_sort	control of protein synthesis and memory by glun3a-nmda receptors through inhibition of git1/mtorc1 assembly
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/77ce7ee1a4f040119c91bf9ba1582051
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Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly

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