Control of protein synthesis and memory by GluN3A-NMDA receptors through inhibition of GIT1/mTORC1 assembly
Por:
Conde-Dusman, M, Dey, P, Elia-Zudaire, O, Rabaneda, L, Garcia-Lira, C, Grand, T, Briz, V, Velasco, E, Andero, R, Ninerola, S, Barco, A, Paoletti, P, Wesseling, J, Gardoni, F, Tavalin, S and Perez-Otano, I
Publicada:
17 nov 2021
Resumen:
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.
Filiaciones:
Conde-Dusman, M:
Inst Neurociencias UMH CSIC, Alicante, Spain
Univ Navarra, Ctr Invest Med Aplicada CIMA, Pamplona, Spain
Kings Coll London, Ctr Dev Neurobiol, Inst Psychiat, London, England
Dey, P:
Univ Navarra, Ctr Invest Med Aplicada CIMA, Pamplona, Spain
NIH, NEI, Bldg 10, Bethesda, MD 20892 USA
Elia-Zudaire, O:
Inst Neurociencias UMH CSIC, Alicante, Spain
Rabaneda, L:
Inst Neurociencias UMH CSIC, Alicante, Spain
Univ Navarra, Ctr Invest Med Aplicada CIMA, Pamplona, Spain
IST Austria, Klosterneuburg, Austria
Garcia-Lira, C:
Inst Neurociencias UMH CSIC, Alicante, Spain
Grand, T:
Inst Biol Ecole Normale Super, CNRS, INSERM, Paris, France
Briz, V:
Ctr Biol Mol Severo Ochoa UAM CSIC, Madrid, Spain
Velasco, E:
Univ Autonoma Barcelona, Inst Neurociencies, Parc Tauli Hosp Univ, Unitat Neurociencia Traslac,Inst Invest & Innovac, Bellaterra, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Salud Mental CIBERSAM, Madrid, Spain
ICREA, Barcelona, Spain
Andero, R:
Univ Autonoma Barcelona, Inst Neurociencies, Parc Tauli Hosp Univ, Unitat Neurociencia Traslac,Inst Invest & Innovac, Bellaterra, Spain
Inst Salud Carlos III, Ctr Invest Biomed Red Salud Mental CIBERSAM, Madrid, Spain
ICREA, Barcelona, Spain
Ninerola, S:
Inst Neurociencias UMH CSIC, Alicante, Spain
:
Inst Neurociencias UMH CSIC, Alicante, Spain
Paoletti, P:
Inst Biol Ecole Normale Super, CNRS, INSERM, Paris, France
Wesseling, J:
Inst Neurociencias UMH CSIC, Alicante, Spain
Gardoni, F:
Univ Milan, Dept Pharmacol & Biomol Sci, Milan, Italy
Tavalin, S:
Univ Tennessee, Ctr Hlth Sci, Dept Pharmacol Addict Sci & Toxicol, Memphis, TN 38163 USA
Perez-Otano, I:
Inst Neurociencias UMH CSIC, Alicante, Spain
Univ Navarra, Ctr Invest Med Aplicada CIMA, Pamplona, Spain
Green Submitted, Green Published, gold
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