A critical evaluation of the activity-regulated cytoskeleton-associated protein (Arc/Arg3.1)'s putative role in regulating dendritic plasticity, cognitive processes, and mood in animal models of depression

Abstract

Major depressive disorder (MDD) is primarily conceptualized as a mood disorder but cognitive dysfunction is also prevalent, and may limit the daily function of MDD patients. Current theories on MDD highlight disturbances in dendritic plasticity in its pathophysiology, which could conceivably play a role in the production of both MDD-related mood and cognitive symptoms. This paper attempts to review the accumulated knowledge on the basic biology of the activity-regulated cytoskeleton-associated protein (Arc or Arg3.1), its effects on neural plasticity, and how these may be related to mood or cognitive dysfunction in animal models of MDD. On a cellular level, Arc plays an important role in modulating dendritic spine density and remodeling. Arc also has a close, bidirectional relationship with postsynaptic glutamate neurotransmission, since it is stimulated by multiple glutamatergic receptor mechanisms but also modulates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor internalization. The effects on AMPA receptor trafficking are likely related to Arc's ability to modulate phenomena such as long-term potentiation, long-term depression, and synaptic scaling, each of which are important for maintaining proper cognitive function. Chronic stress models of MDD in animals show suppressed Arc expression in the frontal cortex but elevation in the amygdala. Interestingly, cognitive tasks depending on the frontal cortex are generally impaired by chronic stress, while those depending on the amygdala are enhanced, and antidepressant treatments stimulate cortical Arc expression with a timeline that is reminiscent of the treatment efficacy lag observed in the clinic or in preclinical models. However, pharmacological treatments that stimulate regional Arc expression do not universally improve relevant cognitive functions, and this highlights a need to further refine our understanding of Arc on a subcellular and network level.

Neuropeptide VGF Promotes Maturation of Hippocampal Dendrites That Is Reduced by Single Nucleotide Polymorphisms

“…Spines are the site of fine-tuning synaptic plasticity, whose induction is much faster than that of large-scale dendritic outgrowth. Activity-regulated cytoskeletal protein (Arc) is a BDNF-regulated immediate early gene has been shown to be instrumental in spine dynamics critical for LTP and learning [60]. We have previously shown that Arc is co-regulated with VGF in hippocampal neurons and that TLQP-62 promotes synaptic plasticity in an acute fashion [1].…”

Activity‐regulated cytoskeleton‐associated protein (Arc/Arg3.1) regulates anxiety‐ and novelty‐related behaviors

“…Arc expression is induced in a number of brain regions following emotionally-relevant experiences, including exposure to novelty 23,24 , environmental enrichment 25 , and stressful experiences 26,27 . As such, Arc is well positioned to influence mood-related behaviors.…”

The serotonin transporter and the activity regulated cytoskeleton‐associated protein genes in antidepressant response and resistance: 5‐HTTLPR and other variants

“…ARC was demonstrated to be essential for the maintenance of dendritic spine density and morphology (Balu & Coyle, ; Peebles et al, ). AD treatment seems to impact on ARC expression (Li et al, ), likely exerting an effect on neuroplasticity processes.…”