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Co-agonists differentially tune GluN2B-NMDA receptor trafficking at hippocampal synapses

Abstract : The subunit composition of synaptic NMDA receptors (NMDAR), such as the relative content of GluN2A- and GluN2B-containing receptors, greatly influences the glutamate synaptic transmission. Receptor co-agonists, glycine and D-serine, have intriguingly emerged as potential regulators of the receptor trafficking in addition to their requirement for its activation. Using a combination of single-molecule imaging, biochemistry and electrophysiology, we show that glycine and D-serine relative availability at rat hippocampal glutamatergic synapses regulate the trafficking and synaptic content of NMDAR subtypes. Acute manipulations of co-agonist levels, both ex vivo and in vitro, unveil that D-serine alter the membrane dynamics and content of GluN2B-NMDAR, but not GluN2A-NMDAR, at synapses through a process requiring PDZ binding scaffold partners. In addition, using FRET-based FLIM approach, we demonstrate that D-serine rapidly induces a conformational change of the GluN1 subunit intracellular C-terminus domain. Together our data fuels the view that the extracellular microenvironment regulates synaptic NMDAR signaling.
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https://www.hal.inserm.fr/inserm-02438999
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Joana Ferreira, Thomas Papouin, Laurent Ladepeche, Andrea Yao, Valentin Langlais, et al.. Co-agonists differentially tune GluN2B-NMDA receptor trafficking at hippocampal synapses. eLife, eLife Sciences Publication, 2017, 6, pp.e25492. ⟨10.7554/eLife.25492⟩. ⟨inserm-02438999⟩

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