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Séminaire impromptu - Ana Lisa CarvalhoNMDA receptors regulate AMPA receptor traffic through anchoring of the synaptic proteasome

Abstract :

N-methyl-D-aspartate (NMDA) receptors play a central role
in shaping the strength of synaptic connections throughout development and in mediating synaptic plasticity mechanisms that underlie some forms of learning and memory formation in the central nervous system. In the hippocampus and the neocortex, GluN1 is combined primarily with GluN2A and GluN2B, which are differentially expressed during development and confer distinct molecular and physiological properties to NMDA receptors. The contribution of each subunit to the synaptic traffic of NMDA receptors and therefore to their role during development and in synaptic plasticity is still controversial.

We found a critical role for the GluN2B subunit in regulating NMDA receptor synaptic targeting. In the absence of GluN2B, the synaptic level of AMPA receptors is increased, and accompanied by decreased constitutive endocytosis of GluA1-AMPA receptor and altered levels of several Ubiquitin Proteasome System (UPS) components, in particular decreased levels of proteasome subunits. Enhancing the proteasome activity with a novel proteasome activator rescued the synaptic levels of AMPA receptors in GluN2B(-/-) neurons, revealing that GluN2B-mediated anchoring of the synaptic proteasome is responsible for fine tuning AMPA receptor synaptic levels under basal conditions.

Selected publications

Louros SR, Hooks BM, Litvina L, Carvalho AL*, Chen C* (*Co-corresponding authors) (2014) A role for stargazin in experience-dependent plasticity. Cell Reports (accepted for publication).

Ribeiro LF, Catarino T, Santos SD, Benoist M, van Leeuwen JF, Esteban JA, Carvalho AL (2014) Ghrelin triggers the synaptic incorporation of AMPA receptors in the hippocampus. Proc Natl Acad Sci U S A, 111:E149-158.

Catarino T, Ribeiro L, Santos SD, Carvalho AL (2013) Regulation of Synapse Composition by Protein Acetylation: The Role of Acetylated Cortactin. J Cell Sci. 126, 149–162.

Santos SD, Iuliano O, Ribeiro L, Veran J, Ferreira JS, Rio P, Mulle C, Duarte CB, Carvalho AL (2012) Contactin associated protein 1 (Caspr1) regulates the traffic and synaptic content of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors. J Biol Chem. 287(9):6868-77.

Ferreira JS, Rooyakkers A, She K, Ribeiro L, Carvalho AL*, Craig AM* (2011) Activity and protein kinase C regulate synaptic accumulation of NMDA receptors independently of GluN1 splice variant. J. Biol. Chem. 286(32):28331-42. *Corresponding authors.