Journal
NEURON
Volume 79, Issue 2, Pages 293-307Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2013.05.003
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Funding
- BBSRC
- MRC
- Wellcome Trust
- WCU Program (Korea)
- BBSRC [BB/H014284/1] Funding Source: UKRI
- MRC [G0501455, G0601813, MC_G1000734] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/H014284/1] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/E500110/1] Funding Source: researchfish
- Medical Research Council [MC_G1000734, G0601841B, G0601813, G0501455] Funding Source: researchfish
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Inhibition of Arp2/3-mediated actin polymerization by PICK1 is a central mechanism to AMPA receptor (AMPAR) internalization and long-term depression (LTD), although the signaling pathways that modulate this process in response to NMDA receptor (NMDAR) activation are unknown. Here, we define a function for the GTPase Arf1 in this process. We show that Arf1-GTP binds PICK1 to limit PICK1-mediated inhibition of Arp2/3 activity. Expression of mutant Arf1 that does not bind PICK1 leads to reduced surface levels of GluA2-containing AMPARs and smaller spines in hippocampal neurons, which occludes subsequent NMDA-induced AMPAR internalization and spine shrinkage. In organotypic slices, NMDAR-dependent LTD of AMPAR excitatory postsynaptic currents is abolished in neurons expressing mutant Arf1. Furthermore, NMDAR stimulation downregulates Arf1 activation and binding to PICK1 via the Arf-GAP GIT1. This study defines Arf1 as a critical regulator of actin dynamics and synaptic function via modulation of PICK1.
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