Wen-Xue Liu1, Jing Wang1, Ze-Min Xie1,2,3, Ning Xu1,2,3, Guang-Fen Zhang1, Min Jia1, Zhi-Qiang Zhou1, Kenji Hashimoto4, Jian-Jun Yang5,6,7. 1. Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China. 2. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China. 3. Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou, China. 4. Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. hashimoto@faculty.chiba-u.jp. 5. Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China. yjyangjj@126.com. 6. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China. yjyangjj@126.com. 7. Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou, China. yjyangjj@126.com.
Abstract
RATIONALE: 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.
RATIONALE: 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 depressedpatients. 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: Ronald C Kessler; Patricia Berglund; Olga Demler; Robert Jin; Doreen Koretz; Kathleen R Merikangas; A John Rush; Ellen E Walters; Philip S Wang Journal: JAMA Date: 2003-06-18 Impact factor: 56.272
Authors: T Kreisel; M G Frank; T Licht; R Reshef; O Ben-Menachem-Zidon; M V Baratta; S F Maier; R Yirmiya Journal: Mol Psychiatry Date: 2013-12-17 Impact factor: 15.992
Authors: Sungho Maeng; Carlos A Zarate; Jing Du; Robert J Schloesser; Joseph McCammon; Guang Chen; Husseini K Manji Journal: Biol Psychiatry Date: 2007-07-23 Impact factor: 13.382
Authors: André R S Colla; Francis L Pazini; Vicente Lieberknecht; Anderson Camargo; Ana Lúcia S Rodrigues Journal: Metab Brain Dis Date: 2021-01-04 Impact factor: 3.584
Authors: Amanda M Dossat; Marcos A Sanchez-Gonzalez; Andrew P Koutnik; Stefano Leitner; Edda L Ruiz; Brittany Griffin; Jens T Rosenberg; Samuel C Grant; Francis D Fincham; Jose R Pinto; Mohamed Kabbaj Journal: FASEB J Date: 2017-02-24 Impact factor: 5.191
Authors: Caren J Blacker; Vincent Millischer; Lauren M Webb; Ada M C Ho; Martin Schalling; Mark A Frye; Marin Veldic Journal: Mol Neuropsychiatry Date: 2019-07-23