The Arc of cognition: Signaling cascades regulating Arc and implications for cognitive function and disease

Semin Cell Dev Biol. 2018 May;77:63-72. doi: 10.1016/j.semcdb.2017.09.023.


The activity-regulated cytoskeletal (Arc) gene is implicated in numerous synaptic plasticity paradigms, including long-term potentiation and depression and homeostatic plasticity, and is critical for consolidating memory. How Arc facilitates these forms of plasticity is not fully understood. Unlike other neuronal immediate-early genes, Arc encodes a protein that shuttles between the somatodendritic and nuclear compartments to regulate synaptic plasticity. Little attention has been paid to Arc's role in the nucleus. Here, we highlight the regulatory elements and signaling cascades required to induce Arc transcription and discuss the significance of Arc nuclear localization for synaptic plasticity and scaling. We integrate these findings into the context of cognitive function and disease and propose a model in which Arc mediates an effect on memory as a "chaser" of synaptic activity through homeostatic scaling.

Keywords: Arg3.1; Homeostatic plasticity; Hyperexcitability; Immediate early gene; Promoter; Transcriptional regulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Active Transport, Cell Nucleus / physiology
  • Cell Nucleus / metabolism
  • Cognition / physiology*
  • Cognition Disorders / pathology*
  • Cytoskeletal Proteins / metabolism*
  • Humans
  • Memory / physiology*
  • Nerve Tissue Proteins / metabolism*
  • Neuronal Plasticity / physiology*
  • Neurons / metabolism
  • Protein Biosynthesis / genetics
  • Signal Transduction / physiology
  • Synapses / metabolism


  • Cytoskeletal Proteins
  • Nerve Tissue Proteins
  • activity regulated cytoskeletal-associated protein