Arc in synaptic plasticity: from gene to behavior

Abstract

The activity-regulated cytoskeletal (Arc) gene encodes a protein that is critical for memory consolidation. Arc is one of the most tightly regulated molecules known: neuronal activity controls Arc mRNA induction, trafficking and accumulation, and Arc protein production, localization and stability. Arc regulates synaptic strength through multiple mechanisms and is involved in essentially every known form of synaptic plasticity. It also mediates memory formation and is implicated in multiple neurological diseases. In this review, we will discuss how Arc is regulated and used as a tool to study neuronal activity. We will also attempt to clarify how its molecular functions correspond to its requirement in various forms of plasticity, discuss Arc's role in behavior and disease, and highlight critical unresolved questions.

Figure 1. Regulation of Arc expression

Signaling through NMDARs [35], Trk-B receptors [26, 27], and mGluRs [29, 30] promotes Arc transcription through one or several downstream signaling kinases, including PKA and ERK. ERK acts through a coactivator, such as TCF, to activate SRF, which binds a SRE in the Arc promoter to increase transcription [27, 37]. ERK also acts through a Zeste-like factor, which binds a ZRE [27]. PKA acts near the SRF site through an unidentified enhancer element. The region surrounding the Arc gene also contains partial CRE and MEF2 sites [37] and CpG sites that mediate epigenetic modifications of Arc transcription [83]. REs in the promoter of Arc [27], and signaling-pathways induced after AMPAR activation [32], inhibit transcription. ERK signaling and signaling pathways activated by NMDARs [47] and mGluR1s [30] promote Arc translation. Arc protein is ubiquitinated by UBE3A [52], which targets it to the proteasome for degradation. Question marks indicate relationships for which the supporting evidence is limited or indirect, or has not been specifically linked to Arc expression. Abbreviations: cAMP cyclic adenosine monophosphate, mAChR muscarinic acetylcholine receptor; Trk-B tropomycin-receptor-kinase; mGluR1 metabatropic glutamate receptor; PKA protein kinase A; PKC protein kinase C; RE repressor element; ZRE Zest-like-response element; SRE serum-response element, MNK1 mitogen-activated protein kinase-interacting kinase, eEIF4E eukaryotic initiation factor 4E, eEF2K eukaryotic elongation factor 2 kinase, eEF2 eukaryotic elongation factor 2, UBE3A ubiquitin protein ligase E3A, Ub ubiquitin.

Figure 2. Cellular functions of Arc

Interactions with other proteins might mediate Arc’s function in LTP, LTD, and structural plasticity. Arc may interact with Wave3 (Peebles, C. Rao, V., Breck, J., Finkbeiner, S. 2008, Society for Neuroscience abstract, 763.20), which could allow it to regulate spine morphology, increasing the proportion of thin spines and decreasing stubby spines [16]. Arc is known to form a complex with endophilin and dynamin that increases the rate of endocytosis of AMPARs [13, 14], possibly mediating Arc’s affects on long term depression. The Arc and dynamin complex cleaves the Notch receptor to activate Notch signaling pathways [15], which might be involved in synaptic depression and potentiation. Arc protein is also present in the nucleus where it promotes the formation of PML-NBs through βSpectrinIV [11], which currently have unknown functions in neurons. Abbreviations: LTP long-term potentation, LTD long-term depression, PML-NB promyelocytic leukemia nuclear body.