Journal
ELIFE
Volume 10, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.71575
Keywords
GluN3A; NMDA receptor; mTOR; protein synthesis; memory; GIT1; synapse; BDNF; Rat; Mouse
Categories
Funding
- H2020 European Research Council ERC [693021]
- Ministerio de Economia, Industria y Competitividad, Gobierno de Espana [SAF2016-76565-R, SAF2017-87928-R, CSD2008-00005, SAF2013-48983R, SAF2016-80895r, RYC2014-15784, SEV-2013-0317, SEV-2017-0723, BFU-2016-80918-R]
- Generalitat Valenciana [PROMETEO 2019/020]
- National Institutes of Health [NS76637]
- University of Tennessee UTHSC College of Medicine Funds
- Agence Nationale de la Recherche [GluBrain3A]
- Instituto de Salud Carlos III [AC19/00077]
- Brain and Behavior Research Foundation NARSAD Independent Investigator Award
- Agencia Estatal de Investigacion [PID2019-111112RB-I00]
- European Research Council (ERC) [693021] Funding Source: European Research Council (ERC)
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The study reveals that synaptic protein synthesis can be regulated by controlling the complex formation of GIT1/mTOR and the binding of NMDA receptors containing GluN3A subunits. Removing GluN3A enhances mTOR-dependent protein synthesis, facilitating memory consolidation. The findings provide insight into synaptic translational control and suggest a potential target for cognitive enhancement.
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.
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