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

eLife

Victor Briz¹  Partha N Dey²  Fabrizio Gardoni³  Steven J Tavalin⁴  Teddy Grand⁵  Pierre Paoletti⁵  Eric R Velasco⁶  Raül Andero Galí⁶  John F Wesseling⁷  Angel Barco⁷  Carmen García-Lira⁷  Sergio Niñerola⁷  Óscar Elía-Zudaire⁷  Isabel Perez-Otaño⁸  María J Conde-Dusman⁹  Luis G Rabaneda^1,10 

[1] Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Madrid, Spain;Centro de Investigación Médica Aplicada (CIMA), University of Navarra, Pamplona, Spain;National Eye Institute, National Institutes of Health, Bethesda, United States;Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy;Department of Pharmacology, Addiction Science, and Toxicology, University of Tennessee Health Science Center, Memphis, United States;Institut de Biologie de l’Ecole Normale Supérieure/CNRS/INSERM, Paris, France;Institut de Neurociències, Departament de Psicobiologia i de Metodologia de les Ciències de la Salut, Unitat de Neurociència Traslacional, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT), Universitat Autònoma de Barcelona, Bellaterra, Spain;Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain;ICREA, Barcelona, Spain;lnstituto de Neurociencias (UMH-CSIC), Alicante, Spain;lnstituto de Neurociencias (UMH-CSIC), Alicante, Spain;Centro de Investigación Médica Aplicada (CIMA), University of Navarra, Pamplona, Spain;lnstituto de Neurociencias (UMH-CSIC), Alicante, Spain;Centro de Investigación Médica Aplicada (CIMA), University of Navarra, Pamplona, Spain;Centre for Developmental Neurobiology, Institute of Psychiatry, King’s College London, London, United Kingdom;lnstituto de Neurociencias (UMH-CSIC), Alicante, Spain;Centro de Investigación Médica Aplicada (CIMA), University of Navarra, Pamplona, Spain;Institute of Science and Technology Austria, Klosterneuburg, Austria;

关键词: GluN3A;    NMDA receptor;    mTOR;    protein synthesis;    memory;    GIT1;    synapse;    BDNF;    Rat;    Mouse;   

DOI  :  10.7554/eLife.71575

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY