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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Bibliographic Details
Published in:	eLife Vol. 10
Main Authors:	Conde-Dusman, María J, Dey, Partha N, Elía-Zudaire, Óscar, Rabaneda, Luis G, García-Lira, Carmen, Grand, Teddy, Briz, Victor, Velasco, Eric R, Andero, Raül, Niñerola, Sergio, Barco, Angel, Paoletti, Pierre, Wesseling, John F, Gardoni, Fabrizio, Tavalin, Steven J, Perez-Otaño, Isabel
Format:	Journal Article
Language:	English
Published:	England eLife Science Publications, Ltd 17-11-2021 eLife Sciences Publications Ltd eLife Sciences Publications, Ltd
Subjects:	Animals Antibodies Brain-derived neurotrophic factor Cell Biology Cognitive ability Female Gene expression GIT1 GluN3A Glutamic acid receptors (ionotropic) Kinases Male Mechanistic Target of Rapamycin Complex 1 Memory Memory - physiology Mice Mice, Inbred C57BL Mice, Transgenic mTOR N-Methyl-D-aspartic acid receptors Neurons NMDA receptor Phosphorylation Protein biosynthesis Protein Biosynthesis - physiology Protein synthesis Proteins Rapamycin Receptors, N-Methyl-D-Aspartate - metabolism Signal Transduction TOR protein TOR Serine-Threonine Kinases - metabolism Variance analysis Spain mouse cell biology memory rat BDNF mTOR protein synthesis synapse GluN3A NMDA receptor GIT1
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Summary:	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.
Bibliography:	These authors contributed equally to this work.
ISSN:	2050-084X 2050-084X
DOI:	10.7554/eLife.71575