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.
Highlights
Cognitive dysfunction is a common aspect of central nervous system diseases that has large implications for patients’ daily life function and adds to the socio-economic burden of psychiatric illness
These data suggest that Arc expression has a dual role in the regulation of synaptic strength, with a transient effect involved in creating new dendritic spines followed by a slower, longer lasting role that tends to reduce the postsynaptic consequences of glutamatergic neurotransmission
It is perhaps not surprising to find that brain-derived neurotrophic factor (BDNF) can increase Arc expression, a phenomenon that has been observed in cultured neurons (Yasuda et al, 2007), in synaptoneurosome preparations (Yin et al, 2002), or in vivo in the cortex (Benekareddy et al, 2013) or dentate gyrus (Wibrand et al, 2006) of rodents
Summary
Cognitive dysfunction is a common aspect of central nervous system diseases that has large implications for patients’ daily life function and adds to the socio-economic burden of psychiatric illness. In addition to a relationship between neuroplasticity and cognitive function, emerging hypotheses on the mechanistic basis for mood dysfunction prominently feature disturbances in neuroplasticity (Pittenger and Duman, 2008) In support of these ideas, there is evidence linking altered neural plasticity to clinical populations. A recent meta-analysis confirmed that reduced volumes are present in the prefrontal cortex, orbitofrontal cortex and cingulate cortex of depressed patients (Arnone et al, 2012), and there is evidence for increased amygdala volume in some MDD populations (Saleh et al, 2012) These volumetric data from human depressed patients are mirrored in non-clinical animal models of depression, which have shown reductions in hippocampal volume after chronic exposure to stressors (Lee et al, 2009) or glucocorticoids (Sousa et al, 1998). This paper seeks to review the accumulated knowledge on the role of Arc in terms of its relationship to neuronal plasticity and cognitive function, as it may relate to MDD
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
