TY - JOUR
T1 - 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
AU - Li, Yan
AU - Pehrson, Alan L.
AU - Waller, Jessica A.
AU - Dale, Elena
AU - Sanchez, Connie
AU - Gulinello, Maria
N1 - Publisher Copyright:
© 2015 Li, Pehrson, Waller, Dale, Sanchez and Gulinello.
PY - 2015
Y1 - 2015
N2 - 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 a-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.
AB - 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 a-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.
KW - Arc
KW - Arg3.1
KW - Cognition
KW - Major Depressive Disorder
KW - Neuroplasticity
UR - http://www.scopus.com/inward/record.url?scp=84938320876&partnerID=8YFLogxK
U2 - 10.3389/fnins.2015.00279
DO - 10.3389/fnins.2015.00279
M3 - Review article
AN - SCOPUS:84938320876
SN - 1662-4548
VL - 9
JO - Frontiers in Neuroscience
JF - Frontiers in Neuroscience
IS - JUL
M1 - 279
ER -