PFC gap junction dysfunction induces depressionJ-D Sun et alNeuropsychopharmacology (2012) 37, 1305-1320 2012 American College of Neuropsychopharmacology. All nghts reserved 0893-133X/I2 www.neuropsychopharmacology.orgGap Junction Dysfunction in the Prefrontal Cortex Induces Depressive-Like Behaviors in RatsJian-Dong Sun1, Yan Liu_, Yu-He Yuan1, Jing Li1 and Nai-Hong Chen*，1State Key Laboratory of Bioactive Substances and Functions of Natural Meaicmes, Deportment of Pharmacology, Institute of Materia Medico, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaGrowing 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 dencits 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 junclional 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 peptiaes 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.Neuropsychopharmacology (2012) 37, 1305-1320; doi: 10.1038/npp.201 1.319; published online 21 December 2011Keywords: gap junction; depression; connexin 43; chronic unpredictable stress; antidepressant; glucocorticoid receptorNeuropsychopharmacologyINTRODUCTIONMajor depressive disorder (MDD) is a common and disabling illness affecting a rising percentage of the worlds population. Growing evidence indicates that glial elements are involved in the neuropathology of several neuropsychiatric illnesses including MDD (Rajkowska and Miguel-Hidalgo, 2007). Post-mortem studies of tissues from patients with MDD describe a reduced number and an altered morphology of glial cells in several brain regions, in particular，the prefrontal cortex (PFC) (Ongur et aly 1998; Rajkowska et aly 1999; Cotter et aly 2001, 2002). Recent studies provide evidence that stress exposure maybe related to some of the reported glial cell pathology by demonstrating that animals exposed to chronic stress have a decreased glial density in the hippocampus (Czeh et aly 2006) and a Correspondence: Professor N-H Chen, Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, I Xiannongtan Street. Xuanwu District, Beijing 100050, China, Tel: +86 10 63165177, Fax: +86 10 63165177, E-mail: chennhimm.ac.cnReceived 28 July 2011; revised 23 November 2011; accepted 25 November 201 I reduced density of astrocytes in the prelimbic region of PFC (prelimbic cortex (PLC); Banasr and Duman, 2008). Altered number and morphology of glial cells may be the cause or consequence of glial dysfunction, and the lower densities of glial cells suggest that dencient or compromised glial function in the PFC may contribute to the symptoms of depression.Glia and，in particular, astrocytes are organized as networks and communicate through specialized channels, the so-called gap junctions (Giaume et aly 2010). Gap junctional channels (GJCs) are composed of connexin (Cx) proteins- There are a wide variety of Cxs synthesized in the nervous system, and it is still a matter of controversy which Cxs are present in specific cell types. At least one, Cx43, is mostly acknowledged to be synthesized in astrocytes (Dermietzel et aly 1991; Giaume et aly 1991). GJCs are permeable to endogenous bioactive cytoplasmic molecules, and therefore the GJC-based astrocytic syncytium provides homeostatic and metabolic support likely essential for physiological neuronal function (Kimelberg 2007). Hereby, we hypothesize that impaired ga