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

作者：Scholz Ralf; Berberich Sven; Rathgeber Louisa; Kolleker Alexander; Koehr Georg; Kornau Hans Christian^*

来源：Neuron, 2010, 66(5): 768-780.

DOI：10.1016/j.neuron.2010.05.003

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.

• 出版日期2010-6-10
• 单位河北医科大学