Rapid Translation of Arc/Arg3.1 Selectively Mediates mGluR-Dependent LTD through Persistent Increases in AMPAR Endocytosis Rate

Abstract

Salient stimuli that modify behavior induce transcription of Activity regulated cytoskeleton-associated protein (Arc/Arg3.1) and transport Arc mRNA into dendrites, suggesting that local Arc translation mediates synaptic plasticity encoding such stimuli. Here we demonstrate that long-term synaptic depression (LTD) in hippocampal neurons induced by group 1 metabotropic glutamate receptors (mGluRs) relies on rapid translation of Arc. MGluR-LTD induction causes long-term increases in AMPA receptor endocytosis rate and dendritic synthesis of Arc, a component of AMPAR endocytosis machinery. Knockdown of Arc prevents mGluRs from triggering AMPAR endocytosis or LTD, and acute blockade of new Arc synthesis with antisense oligonucleotides blocks mGluR-LTD and AMPAR trafficking. In contrast, LTD induced by NMDA receptors does not persistently alter AMPAR endocytosis rate, induce Arc synthesis, or require Arc protein. These data demonstrate a role for local Arc synthesis specifically in mGluR-LTD and suggest that mGluR-LTD may be one consequence of Arc mRNA induction during experience.

Cocaine and Amphetamine Induce Overlapping but Distinct Patterns of AMPAR Plasticity in Nucleus Accumbens Medium Spiny Neurons

“…For example, activity-regulated cytoskeletal associated (Arc) protein is synthesized within dendrites in an activity-and group I mGluR-dependent manner where it associates with components of AMPAR endocytosis machinery and has been shown to actively maintain LTD (Park et al, 2008;Waung et al, 2008). Within striatal regions, Arc protein expression is robustly induced following re-exposure to cocaine-paired stimuli and modulates extinction of drugseeking behavior (Hearing et al, 2011;Hearing et al, 2008).…”

Pharmacological Rescue of Cortical Synaptic and Network Potentiation in a Mouse Model for Fragile X Syndrome

“…As FMRP is confirmed to be a repressor of synaptic protein synthesis (Bear et al, 2004;Bhakar et al, 2012), loss of FMRP in FXS may lead to deficits in synaptic plasticity and information storage. Indeed, it has been reported that FMRP can negatively regulate proteins that trigger AMPA receptor internalization (Park et al, 2008;Waung et al, 2008), and Fmr1 knockout (KO) mice display exaggerated long-term depression in the hippocampus (Huber et al, 2002;Zhang et al, 2009) and cerebellum (Koekkoek et al, 2005).…”

Class I Histone Deacetylase-mediated Repression of the Proximal Promoter of the Activity-regulated Cytoskeleton-associated Protein Gene Regulates Its Response to Brain-derived Neurotrophic Factor

“…In neurons, Arc expression is regulated by various stimuli including not only neuronal activity, but also BDNF, cAMP, and PDGF (3)(4)(5)(6). Arc mRNA has been detected in cell bodies, dendrites, and spines after stimulation (7,8), and the Arc protein could be synthesized locally at dendritic spines (9,10). Arc is known to be required for the endocytosis of AMPA receptors (10) and for long-term potentiation (LTP)-induced F-actin stabilization (9,11).…”

“…Arc mRNA has been detected in cell bodies, dendrites, and spines after stimulation (7,8), and the Arc protein could be synthesized locally at dendritic spines (9,10). Arc is known to be required for the endocytosis of AMPA receptors (10) and for long-term potentiation (LTP)-induced F-actin stabilization (9,11). Okuno et al (12) reported that Arc plays a role in the inverse synaptic tagging of silent synapses; Arc accumulated in silent synapses to reduce surface AMPA receptors (12).…”

“…Okuno et al (12) reported that Arc plays a role in the inverse synaptic tagging of silent synapses; Arc accumulated in silent synapses to reduce surface AMPA receptors (12). Thus, Arc is a unique molecule involved in the control of synaptic plasticity (10,13,14). Kawashima et al (4) demonstrated that a distal enhancer, synaptic activity-responsive element (SARE), which contains binding sites for cAMP-response element (CRE)-binding protein (CREB), myocyte enhancer factor 2 (MEF2), and serum response factor (SRF), located Ϫ7 kbp upstream of the Arc transcription start site, was essential for activity-dependent transcriptional activation of Arc (4).…”