title: A novel cognitive impairment mechanism that astrocytic p-connexin 43 promotes neuronic autophagy via activation of P2X7R and down-regulation of GLT-1 expression in the hippocampus following traumatic brain injury in rats.
abstract: Connexin 43 (Cx43) is one of the major gap junction proteins in astrocytes. Our previous studies reported that astrocytic phosphorylated Cx43 (p-CX43) regulated neuronic autophagy levels in the rat hippocampus after traumatic brain injury (TBI). In this study, we explored the underlying molecular mechanism by which gap junctional intercellular communication influenced neuronic autophagy and therefore initiated cognitive and memory impairments after TBI. The gap junctional blocker carbenoxolone (CBX) or autophagy inhibitor 3-methyladenine (3-MA) reduced latencies, as compared to TBI rats. Similarly, CBX or 3-MA restored long-term potentiation (LTP), relative to TBI hippocampal slices. Immunoblotting analysis showed that the expression of autophagy-related gene Beclin-1 in the hippocampus post-TBI were decreased in response to treatment with CBX, the P2X7 receptor (P2X7R) antagonist Oxidized ATP (OxATP) or ceftriaxone (Cef) which increased the expression and activity of the glutamate transporter (GLT-1) in the central nervous system (CNS). Moreover, CBX or OxATP pretreatment increased GLT-1 level in the rat hippocampus after TBI. However, CBX pretreatment suppressed P2X7R expression whereas maintained P2X7 level post-TBI. Confocal images revealed that p-CX43, P2X7 and GLT-1 strongly colocalized with glial fibrillary acidic protein (GFAP). Taken together, these results implied that Cx43, might induce neuronic autophagy by activation of P2X7R and reduce the expression of GLT-1 in the hippocampus, promoting TBI-induced cognitive deficits repair. Therefore, control of this communication may be serve as therapeutic strategies for intervention against TBI.
authors.affiliation: Department of Interventional Neuroradiology, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China.
authors.forename: Liqian
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Science, North China University Science And Technology, Tangshan 063000, Hebei, China.
authors.forename: Junling
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Science, North China University Science And Technology, Tangshan 063000, Hebei, China.
authors.forename: Manman
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Neurosurgery, Tangshan Gongren Hospital, Tangshan 063000, Hebei, China.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Cui
authors.affiliation: Department of Interventional Neuroradiology, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China.
authors.forename: Youxiang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Interventional Neuroradiology, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China.
authors.forename: Xinjian
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Ophthalmology, Tangshan Ophthalmology Hospital, Tangshan 063000, Hebei, China.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Jing
authors.affiliation: Department of Interventional Neuroradiology, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China. Electronic address: zhongxuewu@yeah.net.
authors.forename: Zhongxue
authors.initials: Z
authors.lastname: Wu
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D018031:Connexin 43 / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D010766:Phosphorylation; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D046509:Tissue Culture Techniques
chemical_list: D018031:Connexin 43; D027342:Excitatory Amino Acid Transporter 2; C580592:Gja1 protein, rat; D005904:Glial Fibrillary Acidic Protein; C546470:P2rx7 protein, rat; D058486:Receptors, Purinergic P2X7; C493395:Slc1a2 protein, rat
keywords: Autophagy; Cognitive function; Hippocampal slices; Hippocampus; Traumatic brain injury