title: Regulation of glutamate transporter 1 via BDNF-TrkB signaling plays a role in the anti-apoptotic and antidepressant effects of ketamine in chronic unpredictable stress model of depression.
abstract: BACKGROUND
  Growing evidence suggests that downregulated clearance of glutamate and signaling pathways involving brain-derived neurotrophic factor (BDNF) and its receptor TrkB play a role in morphological changes in the hippocampus of depressed patients. The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is the most attractive antidepressant, although precise mechanisms are unknown.
  
  
  OBJECTIVE
  In this study, we examined whether hippocampal BDNF-TrkB signaling underlies the antidepressant effects of ketamine via upregulating glutamate transporter 1 (GLT-1) in rats, subjected to the chronic unpredictable stress (CUS) for 42 days. The rats received a single injection of ketamine (10 mg/kg, i.p.) and/or a TrkB inhibitor, K252a (1 μl, 2 mM, intracerebroventicular (i.c.v.)) on day 43. Behavioral tests and brain sample collection were evaluated 24 h later.
  
  
  RESULTS
  The CUS-exposed rats exhibited depression- and anxiety-like behaviors; decreased number of glial fibrillary acidic protein (GFAP)-positive (but not NeuN-positive) cells in the dentate gyrus (DG), CA1, and CA3 areas; increased number of cleaved caspase-3-positive astrocytes; reduced spine density; lower ratio of Bcl2 to Bax; and decreased levels of BDNF, phosphorylated cAMP response element binging protein (CREB), GLT-1, and postsynaptic density 95 (PSD95) proteins in the hippocampus. Ketamine alleviated the CUS-induced abnormalities. The effects of ketamine were antagonized by pretreatment with K252a.
  
  
  CONCLUSIONS
  Our findings suggest that regulation of GLT-1 on astrocytes, responsible for 90 % of glutamate reuptake from the synapse, through BDNF-TrkB signaling is involved in mediation of the therapeutic effects of ketamine on behavioral abnormalities and morphological changes in the hippocampus of the CUS-exposed rats.
authors.affiliation: Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
authors.forename: Wen-Xue
authors.initials: WX
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.|Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China.|Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou, China.
authors.forename: Ze-Min
authors.initials: ZM
authors.lastname: Xie
authors.affiliation: Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.|Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China.|Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
authors.forename: Guang-Fen
authors.initials: GF
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
authors.forename: Min
authors.initials: M
authors.lastname: Jia
authors.affiliation: Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Zhou
authors.affiliation: Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. hashimoto@faculty.chiba-u.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hashimoto
authors.affiliation: Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China. yjyangjj@126.com.|Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China. yjyangjj@126.com.|Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou, China. yjyangjj@126.com.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Yang
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology; D002908:Chronic Disease; D003866:Depressive Disorder / Q000188:drug therapy* / Q000523:psychology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D027342:Excitatory Amino Acid Transporter 2 / Q000096:biosynthesis* / Q000235:genetics*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D026121:Indole Alkaloids / Q000494:pharmacology; D007276:Injections, Intraventricular; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013315:Stress, Psychological / Q000378:metabolism* / Q000523:psychology*
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D018691:Excitatory Amino Acid Antagonists; D027342:Excitatory Amino Acid Transporter 2; D026121:Indole Alkaloids; C493395:Slc1a2 protein, rat; D007649:Ketamine; C049985:staurosporine aglycone; D020813:Receptor, trkB
keywords: Apoptosis; BDNF-TrkB signaling; Glutamate transporter; Hippocampus; Ketamine