title: Orbitofrontal cortex 5-HT2A receptor mediates chronic stress-induced depressive-like behaviors and alterations of spine density and Kalirin7.
abstract: Neuroimaging studies show that patients with major depression have reduced volume of the orbitofrontal cortex (OFC). Although the serotonin (5-HT) 2A receptor, which is abundant in the OFC, has been implicated in depression, the underlying mechanisms in the development of stress-induced depression remain unclear. Kalirin-7 (Kal7) is an essential component of mature excitatory synapses for maintaining dendritic spines density, size and synaptic functions. The aim of this study was to investigate the role of orbitofrontal 5-HT and 5-HT2A receptors in depressive-like behaviors and their associations with Kal7 and dendritic spines using chronic unpredictable mild stress (CUMS), an established animal model of depression. CUMS had no effect on the levels of 5-HT or the 5-HT2A receptor in the OFC. However, CUMS or microinjection of the 5-HT2A/2C receptor agonist (±)-1-(2, 5-Dimethoxy-4-iodophenyl)- 2-aminopropane hydrochloride (DOI, 5 μg/0.5 μL) into the OFC induced depressive-like behaviors, including anhedonia in the sucrose preference test and behavioral despair in the tail suspension test, a significant reduction in body weight gain and locomotor activity in the open field test, which were accompanied by decreased expression of Kal7 and PSD95 as well as decreased density of dendritic spines in the OFC. These alterations induced by CUMS were reversed by pretreatment with the 5-HT2A receptor antagonist Ketanserin (Ket, 5 μg/0.5 μL into the OFC). These results suggest that CUMS alters structural plasticity through activation of the orbital 5-HT2A receptor and is associated with decreased expression of Kal7, thereby resulting in depressive-like behaviors in rats, suggesting an important role of Kal7 in the OFC in depression.
authors.affiliation: College of Life Science, Shaanxi Normal University, Xi'an, Shaanxi 710119, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Xu
authors.affiliation: College of Life Science, Shaanxi Normal University, Xi'an, Shaanxi 710119, China; University of Connecticut Health Center, Department of Neuroscience, Farmington, CT 06030, USA.
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Ma
authors.affiliation: College of Life Science, Shaanxi Normal University, Xi'an, Shaanxi 710119, China.
authors.forename: Hui-Bin
authors.initials: HB
authors.lastname: Chen
authors.affiliation: College of Life Science, Shaanxi Normal University, Xi'an, Shaanxi 710119, China.
authors.forename: Meng-He
authors.initials: MH
authors.lastname: Zhou
authors.affiliation: College of Life Science, Shaanxi Normal University, Xi'an, Shaanxi 710119, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Qiao
authors.affiliation: College of Life Science, Shaanxi Normal University, Xi'an, Shaanxi 710119, China. Electronic address: shuchengan@snnu.edu.cn.
authors.forename: Shu-Cheng
authors.initials: SC
authors.lastname: An
mesh_terms: D000818:Animals; D002908:Chronic Disease; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology; D003863:Depression / Q000378:metabolism* / Q000473:pathology; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D057967:Infusions, Intraventricular; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000008:administration & dosage; D013315:Stress, Psychological / Q000378:metabolism* / Q000473:pathology
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C102365:Kalrn protein, rat; D044402:Receptor, Serotonin, 5-HT2A; D058826:Serotonin 5-HT2 Receptor Agonists
keywords: Chronic unpredictable mild stress (CUMS); Dendritic spines; Depression; Kalirin; Orbitofrontal cortex (OFC); Serotonin 2A receptor (5-HT(2A)R)