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 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.
Scholz
Ralf
R
Center for Molecular Neurobiology (ZMNH), University of Hamburg, Hamburg, Germany.
Berberich
Sven
S
Rathgeber
Louisa
L
Kolleker
Alexander
A
Köhr
Georg
G
Kornau
Hans-Christian
HC
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D022162:Cytoplasmic Vesicles / Q000502:physiology; D004705:Endocytosis / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D006801:Humans; D036881:Long-Term Synaptic Depression / Q000502:physiology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D051381:Rats; D018091:Receptors, AMPA / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D000089982:ADP-Ribosylation Factor 6; D020662:Guanine Nucleotide Exchange Factors; C539984:IQSEC2 protein, mouse; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; C000715727:Arf6 protein, mouse; C000715349:Arf6 protein, rat