Molecular physiology of Arc/Arg3.1: The oligomeric state hypothesis of synaptic plasticity

Abstract

The immediate early gene, Arc, is a pivotal regulator of synaptic plasticity, memory, and cognitive flexibility. But what is Arc protein? How does it work? Inside the neuron, Arc is a protein interaction hub and dynamic regulator of intra‐cellular signaling in synaptic plasticity. In remarkable contrast, Arc can also self‐assemble into retrovirus‐like capsids that are released in extracellular vesicles and capable of intercellular transfer of RNA. Elucidation of the molecular basis of Arc hub and capsid functions, and the relationship between them, is vital for progress. Here, we discuss recent findings on Arc structure–function and regulation of oligomerization that are giving insight into the molecular physiology of Arc. The unique features of mammalian Arc are emphasized, while drawing comparisons with Drosophila Arc and retroviral Gag. The Arc N‐terminal domain, found only in mammals, is proposed to play a key role in regulating Arc hub signaling, oligomerization, and formation of capsids. Bringing together several lines of evidence, we hypothesize that Arc function in synaptic plasticity—long‐term potentiation (LTP) and long‐term depression (LTD)—are dictated by different oligomeric forms of Arc. Specifically, monomer/dimer function in LTP, tetramer function in basic LTD, and 32‐unit oligomer function in enhanced LTD. The role of mammalian Arc capsids is unclear but likely depends on the cross‐section of captured neuronal activity‐induced RNAs. As the functional states of Arc are revealed, it may be possible to selectively manipulate specific forms of Arc‐dependent plasticity and intercellular communication involved in brain function and dysfunction.

Plasticity

“…In turn, organelle plasticity also mediates the downside of exercise adaptation, that is, the negative, pathophysiological mechanisms of a reduction in physical activity. 10 In the CNS, Eriksen et al recently characterized ARC as a "protein interaction hub" in synaptic plasticity, 11 whereas in another study, Popov et al have seen a beneficial effect of dietary fat intake on specifically astrocytic plasticity. 12,13 Yeh et al have looked in depth at adult neurogenesis, a pivotal example of CNS neural plasticity.…”

“…In the CNS, Eriksen et al. recently characterized ARC as a “protein interaction hub” in synaptic plasticity, 11 whereas in another study, Popov et al. have seen a beneficial effect of dietary fat intake on specifically astrocytic plasticity 12,13 .…”

IL-1β, the first piece to the puzzle of sepsis-related cognitive impairment?

“…When BDNF binds to its high-affinity receptor TrkB, it activates cAMP Response Element-Binding Protein (CREB) via the PI3K/Akt signaling pathway and promotes the transcription of Arc and Homer1. Arc and Homer1 facilitate the organization of filamentous actin (F-actin) and remodeling of spines, which are crucial processes for structural alterations of spines and stabilization of the potentiation effect ( Tong et al, 2012 ; Giacobbo et al, 2019 ; Eriksen and Bramham, 2022 ). IL-1β disrupts cytoskeletal alterations and reduces the density of mature spines through the aforementioned p38MAPK signaling pathway ( Tong et al, 2012 ; Herrera et al, 2019 ) ( Figure 2A ).…”

Structural characterization of two nanobodies targeting the ligand-binding pocket of human Arc

“…Arc can oligomerize into virus-like capsids containing Arc mRNA that can be transferred to neighboring cells [ 36 ]. Capsid formation is explained by the retroviral origin of Arc as a repurposed retrotransposon, but the molecular structure and assembly of mammalian Arc capsids is unknown [ 32 , 36 , 37 ]. Overall, the variety of interrelated molecular functions emphasizes the need to further characterize Arc on a structural and functional level.…”