The Arc of synaptic memory

Abstract

The immediate early gene Arc is emerging as a versatile, finely tuned system capable of coupling changes in neuronal activity patterns to synaptic plasticity, thereby optimizing information storage in the nervous system. Here, we attempt to overview the Arc system spanning from transcriptional regulation of the Arc gene, to dendritic transport, metabolism, and translation of Arc mRNA, to post-translational modification, localization, and degradation of Arc protein. Within this framework we discuss the function of Arc in regulation of actin cytoskeletal dynamics underlying consolidation of long-term potentiation (LTP) and regulation of AMPA-type glutamate receptor endocytosis underlying long-term depression (LTD) and homeostatic plasticity. Behaviorally, Arc has a key role in consolidation of explicit and implicit forms of memory, with recent work implicating Arc in adaptation to stress as well as maladaptive plasticity connected to drug addiction. Arc holds considerable promise as a "master regulator" of protein synthesis-dependent forms of synaptic plasticity, but the mechanisms that modulate and switch Arc function are only beginning to be elucidated.

Fig. 1

Arc transcriptional regulation, transport, and docking. Arc expression is induced by signaling cascades that regulate transcription factors in response to synaptic activity. The diagram depicts the genomic organization of the synaptic activity-responsive element (SARE) and other regulatory elements upstream of the Arc open reading frame that serve as binding sites for these transcription factors. Following transcription, cis-regulatory elements of the Arc mRNA regulate its assembly into transport mRNPs. The dendritic localization and stability of the mRNA in dendrites is a result of active microtubule-based transport and local F-actin-dependent docking. Upon translation, Arc RNA is subject to rapid nonsense-mediated RNA decay. A2RE hnRNP A2 response element; BDNF brain-derived neurotrophic factor; CREB CRE-binding protein; CRE cAMP response element; DTE dendritic targeting elements; UTR untranslated region; ERK extracellular signal-regulated kinase; IRES internal ribosome entry site; mACh-R muscarinic acetylcholine receptor; MEF2 myocyte enhancing factor; NMDA-R NMDA-receptor; ORF open reading frame; PKA cAMP-dependent protein kinase; PKC protein kinase C; SRE serum response element; SRF serum response factor

Fig. 2

Arc protein function. a Schematic representation of Arc protein domains and binding motifs. The endophilin and dynamin binding sites mediate AMPAR endocytosis in synaptic depression. The PEST sequence, a region rich in the amino acids proline (P), glutamate (E), serine (S), or threonine (T), could target Arc for proteasomal degradation. b Arc is required for LTP consolidation through regulation of F-actin expansion. F-actin functions in PSD remodeling and spine enlargement, and is recently implicated in the sustained phosphorylation of translation initiation factor eIF4E during LTP. Synaptic depression in homeostatic plasticity and LTD is mediated by AMPAR endocytosis. c Arc functions. Arc plays critical roles in synaptic plasticity and memory storage. Functions in neurogenesis, drug addiction, and resilience to stress have been suggested but causal roles have not been defined

Fig. 3

Sequence of events in Arc-dependent LTP consolidation. This is a working hypothesis based mainly on studies of LTP in the medial perforant path input to granule cells of the rat dentate gyrus. Following LTP induction Arc mRNA is transported to dendrites where it localizes to the actin cytoskeleton within spines of activated synapses. Synaptically evoked ERK signaling coordinates Arc transcription, RNA docking, and translation. Arc synthesis within the spine is necessary for phosphorylation of cofilin and stable expansion of the F-actin network. In turn, regulation of actin dynamics by Arc is necessary for the maintenance of translation initiation factor eIF4E phosphorylation during LTP consolidation. Finally, phosphorylation of eIF4E, formation of the translation initiation complex, and Arc synthesis all require ERK signaling. Taken together, this has the makings of a positive feedback circuit which serves to sustain the local synthesis of Arc during the critical period of LTP consolidation. While not depicted here, it should be noted that BDNF is capable of activating Arc-dependent LTP consolidation. BDNF brain-derived neurotrophic factor; eIF4E eukaryotic initiation factor 4E; ERK extracellular signal-regulated kinase