Yi Wang1, Wei He2, Huiping Zhang2, Zhenyu Yao2, Fengyu Che2, Yanjun Cao3, Hongli Sun4. 1. Department of Neonatal Intensive Care Unit, Xi'an Children's Hospital (The Affiliated Children's Hospital of Xi'an Jiaotong University), Xi'an, Shaanxi, 86-710003, P.R. China. 2. Shaanxi Institute of Pediatric Diseases, Xi'an Key Laboratory of Children's Health and Diseases, Xi'an Children's Hospital (The Affiliated Children's Hospital of Xi'an Jiaotong University), Xi'an, Shaanxi, 86-710003, P.R. China. 3. Key Laboratory of Resource Biology and Biotechnology in Western China (Northwest University), Ministry of Education, Xi'an, Shaanxi, 86-710069, P.R. China. 4. Shaanxi Institute of Pediatric Diseases, Xi'an Key Laboratory of Children's Health and Diseases, Xi'an Children's Hospital (The Affiliated Children's Hospital of Xi'an Jiaotong University), Xi'an, Shaanxi, 86-710003, P.R. China; Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 86-710061, P.R. China. Electronic address: sunhongligo@yeah.net.
Abstract
BACKGROUND: New insights have recently been gained into ketamine's potential anti-depressive effects. However, the mechanisms that underlie ketamine's rapid antidepressant activity still remain a mystery. METHODS: We used a rat prenatal stress (PS) model of depression to explore the functional role of mGluR5 in ketamine's rapidly induced antidepressant activity. Effects of the antidepressants imipramine, escitalopram, ketamine, and fluoxetine were compared. AAV-mGluR5 and AAV-shRNA-mGluR5 were constructed to overexpress and knockdown hippocampal mGluR5 respectively. RESULTS: This study shows that mGluR5, which is associated with depression-like behaviors, is increased in susceptible rats exposed to prenatal stress, and that ketamine could significantly alleviate these stress-induced effects. RU-38486 down-regulated expression of mGluR5 and up-regulated NR1. MPEP and CHPG also altered expression of both mGluR5 and NR1. Notably, hippocampal overexpression of mGluR5 in wild type rats changed NR1 and PSD-95 expression and induced depression-like behavior that could be blocked by ketamine activity. Further, knockdown of hippocampal mGluR5 in PS-S rats restored normal levels of mGluR5, NR1, and PSD-95, and alleviated depression-like behavior. LIMITATIONS: The entire rat hippocampus was used for this study, but the role of mGluR5 may vary by sub-region. CONCLUSION: These results suggest that hippocampal mGluR5 may play a key role in mediating the rapid antidepressant effects of ketamine in a prenatal stress model of depression. This provides a novel therapeutic target in clinical treatment of depression.
BACKGROUND: New insights have recently been gained into ketamine's potential anti-depressive effects. However, the mechanisms that underlie ketamine's rapid antidepressant activity still remain a mystery. METHODS: We used a rat prenatal stress (PS) model of depression to explore the functional role of mGluR5 in ketamine's rapidly induced antidepressant activity. Effects of the antidepressants imipramine, escitalopram, ketamine, and fluoxetine were compared. AAV-mGluR5 and AAV-shRNA-mGluR5 were constructed to overexpress and knockdown hippocampal mGluR5 respectively. RESULTS: This study shows that mGluR5, which is associated with depression-like behaviors, is increased in susceptible rats exposed to prenatal stress, and that ketamine could significantly alleviate these stress-induced effects. RU-38486 down-regulated expression of mGluR5 and up-regulated NR1. MPEP and CHPG also altered expression of both mGluR5 and NR1. Notably, hippocampal overexpression of mGluR5 in wild type rats changed NR1 and PSD-95 expression and induced depression-like behavior that could be blocked by ketamine activity. Further, knockdown of hippocampal mGluR5 in PS-S rats restored normal levels of mGluR5, NR1, and PSD-95, and alleviated depression-like behavior. LIMITATIONS: The entire rat hippocampus was used for this study, but the role of mGluR5 may vary by sub-region. CONCLUSION: These results suggest that hippocampal mGluR5 may play a key role in mediating the rapid antidepressant effects of ketamine in a prenatal stress model of depression. This provides a novel therapeutic target in clinical treatment of depression.