Abstract
SummaryInhibition 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.
Highlights
Long-term synaptic plasticity is thought to underlie learning and memory and is important for the fine-tuning of neural circuitry during development
Inhibition of Arp2/3-mediated actin polymerization by PICK1 is a central mechanism to AMPA receptor (AMPAR) internalization and long-term depression (LTD), the signaling pathways that modulate this process in response to NMDA receptor (NMDAR) activation are unknown
Expression of mutant ADP-ribosylation factor 1 (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
Summary
Long-term synaptic plasticity is thought to underlie learning and memory and is important for the fine-tuning of neural circuitry during development. AMPA receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission in the brain, and plasticity at excitatory synapses involves alterations in AMPAR number at the synaptic plasma membrane in processes involving the regulated trafficking of AMPARcontaining vesicles (Collingridge et al, 2010; Shepherd and Huganir, 2007). The dynamic actin cytoskeleton is central to the regulation of vesicle trafficking by exerting mechanical forces that alter membrane geometry (Kaksonen et al, 2006). The dynamic actin cytoskeleton plays a crucial role in the regulation of AMPAR trafficking that underlies synaptic plasticity (Cingolani and Goda, 2008); the mechanisms that regulate actin polymerization to control AMPAR trafficking during synaptic plasticity are not well understood
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