Neuron
Volume 79, Issue 2, 24 July 2013, Pages 293-307
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Article
The Small GTPase Arf1 Modulates Arp2/3-Mediated Actin Polymerization via PICK1 to Regulate Synaptic Plasticity

https://doi.org/10.1016/j.neuron.2013.05.003Get rights and content
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Highlights

  • The Arf1-PICK1-Arp2/3 pathway regulates actin polymerization

  • NMDAR activation activates the Arf-GAP GIT1 to deactivate Arf1

  • Arf1 controls NMDAR-dependent, PICK1-mediated AMPAR trafficking and LTD

  • A noncanonical role is described for Arf1 in vesicle traffic, distinct from COPI regulation

Summary

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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These authors contributed equally to this work