Neuron
Volume 66, Issue 5, 10 June 2010, Pages 768-780
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Article
AMPA Receptor Signaling through BRAG2 and Arf6 Critical for Long-Term Synaptic Depression

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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.

Highlights

► 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

MOLNEURO
SIGNALING

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