title: Gap junction dysfunction in the prefrontal cortex induces depressive-like behaviors in rats.
abstract: Growing evidence has implicated glial anomalies in the pathophysiology of major depression disorder (MDD). Gap junctional communication is a main determinant of astrocytic function. However, it is unclear whether gap junction dysfunction is involved in MDD development. This study investigates changes in the function of astrocyte gap junction occurring in the rat prefrontal cortex (PFC) after chronic unpredictable stress (CUS), a rodent model of depression. Animals exposed to CUS and showing behavioral deficits in sucrose preference test (SPT) and novelty suppressed feeding test (NSFT) exhibited significant decreases in diffusion of gap junction channel-permeable dye and expression of connexin 43 (Cx43), a major component of astrocyte gap junction, and abnormal gap junctional ultrastructure in the PFC. Furthermore, we analyzed the effects of typical antidepressants fluoxetine and duloxetine and glucocorticoid receptor (GR) antagonist mifepristone on CUS-induced gap junctional dysfunction and depressive-like behaviors. The cellular and behavioral alterations induced by CUS were reversed and/or blocked by treatment with typical antidepressants or mifepristone, indicating that the mechanism of their antidepressant action may involve the amelioration of gap junction dysfunction and the cellular changes may be related to GR activation. We then investigated the effects of pharmacological gap junction blockade in the PFC on depressive-like behaviors. The results demonstrate that carbenoxolone (CBX) infusions induced anhedonia in SPT, and anxiety in NSFT, and Cx43 mimetic peptides Gap27 and Gap26 also induced anhedonia, a core symptom of depression. Together, this study supports the hypothesis that gap junction dysfunction contributes to the pathophysiology of depression.
authors.affiliation: State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Department of Pharmacology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Sun
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Yu-He
authors.initials: YH
authors.lastname: Yuan
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Nai-Hong
authors.initials: NH
authors.lastname: Chen
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002229:Carbenoxolone / Q000494:pharmacology; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D000068736:Duloxetine Hydrochloride; D004597:Electroshock / Q000009:adverse effects; D005106:Exploratory Behavior / Q000502:physiology; D005473:Fluoxetine / Q000494:pharmacology; D005508:Food Deprivation; D005518:Food Preferences / Q000502:physiology; D017629:Gap Junctions / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology; D007266:Inhibition, Psychological; D007546:Isoquinolines / Q000378:metabolism; D008297:Male; D046529:Microscopy, Electron, Transmission; D015735:Mifepristone / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000473:pathology*; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley; D012149:Restraint, Physical / Q000009:adverse effects; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D012934:Social Isolation / Q000523:psychology; D013315:Stress, Psychological / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D013395:Sucrose / Q000008:administration & dosage; D013549:Sweetening Agents / Q000008:administration & dosage; D013550:Swimming / Q000523:psychology; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D002229:Carbenoxolone; D018031:Connexin 43; D000068736:Duloxetine Hydrochloride; D005473:Fluoxetine; D005904:Glial Fibrillary Acidic Protein; D006727:Hormone Antagonists; D007546:Isoquinolines; D015735:Mifepristone; D012333:RNA, Messenger; D017367:Selective Serotonin Reuptake Inhibitors; D013395:Sucrose; D013549:Sweetening Agents; D013876:Thiophenes; C017475:lucifer yellow