MGluR5 mediates ketamine antidepressant response in susceptible rats exposed to prenatal stress

Abstract

BackgroundNew 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. MethodsWe 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. ResultsThis 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. LimitationsThe entire rat hippocampus was used for this study, but the role of mGluR5 may vary by sub-region. ConclusionThese 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.