AMPA Receptor Signaling through BRAG2 and Arf6 Critical for Long-Term Synaptic Depression

Central nervous system synapses undergo activity-dependent alterations to support learning and memory. Long-term depression (LTD) reflects a sustained reduction of the synaptic AMPA receptor content based on targeted clathrin-mediated endocytosis. Here we report a current-independent form of AMPA re...

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Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2010-06, Vol.66 (5), p.768-780
Main Authors: Scholz, Ralf, Berberich, Sven, Rathgeber, Louisa, Kolleker, Alexander, Köhr, Georg, Kornau, Hans-Christian
Format: Article
Language:English
Subjects:
ADP-Ribosylation Factors - physiology
Animals
Binding sites
Cell adhesion & migration
Cell culture
Cell Line
Cells, Cultured
Cytoplasmic Vesicles - physiology
Endocytosis - physiology
Guanine Nucleotide Exchange Factors - physiology
Humans
Ligands
Long-Term Synaptic Depression - physiology
Mice
MOLNEURO
Nerve Tissue Proteins - physiology
Neurons
Neurons - physiology
Phosphorylation
Rats
Receptors, AMPA - physiology
Recruitment
Rodents
Signal Transduction - physiology
SIGNALING
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Summary:Central nervous system synapses undergo activity-dependent alterations to support learning and memory. Long-term depression (LTD) reflects a sustained reduction of the synaptic AMPA receptor content based on targeted clathrin-mediated endocytosis. Here we report a current-independent form of AMPA receptor signaling, fundamental for LTD. We found that AMPA receptors directly interact via the GluA2 subunit with the synaptic protein BRAG2, which functions as a guanine-nucleotide exchange factor (GEF) for the coat-recruitment GTPase Arf6. BRAG2-mediated catalysis, controlled by ligand-binding and tyrosine phosphorylation of GluA2, activates Arf6 to internalize synaptic AMPA receptors upon LTD induction. Furthermore, acute blockade of the GluA2-BRAG2 interaction and targeted deletion of BRAG2 in mature hippocampal CA1 pyramidal neurons prevents LTD in CA3-to-CA1 cell synapses, irrespective of the induction pathway. We conclude that BRAG2-mediated Arf6 activation triggered by AMPA receptors is the convergent step of different forms of LTD, thus providing an essential mechanism for the control of vesicle formation by endocytic cargo. ► AMPAR subunit GluA2 directly interacts with BRAG2, a synaptic Arf6-GEF ► BRAG2 activity is controlled by AMPAR ligand binding and tyrosine phosphorylation ► BRAG2-mediated Arf6 activation promotes AMPAR endocytosis ► AMPAR-BRAG2 signaling is essential for hippocampal mGluR- and NMDAR-dependent LTD
ISSN:0896-6273
1097-4199
DOI:10.1016/j.neuron.2010.05.003