变构调节
神经科学
抗抑郁药
变构调节剂
传输(电信)
化学
生物
药理学
计算机科学
受体
海马体
生物化学
电信
作者
Max E. Joffe,Chiaki I. Santiago,Kendra H. Oliver,James Maksymetz,Nicholas B. Harris,Julie L. Engers,Craig W. Lindsley,Danny G. Winder,P. Jeffrey Conn
出处
期刊:Neuron
[Elsevier]
日期:2020-01-08
卷期号:105 (1): 46-59.e3
被引量:51
标识
DOI:10.1016/j.neuron.2019.09.044
摘要
Non-selective antagonists of metabotropic glutamate receptor subtypes 2 (mGlu2) and 3 (mGlu3) exert rapid antidepressant-like effects by enhancing prefrontal cortex (PFC) glutamate transmission; however, the receptor subtype contributions and underlying mechanisms remain unclear. Here, we leveraged newly developed negative allosteric modulators (NAMs), transgenic mice, and viral-assisted optogenetics to test the hypothesis that selective inhibition of mGlu2 or mGlu3 potentiates PFC excitatory transmission and confers antidepressant efficacy in preclinical models. We found that systemic treatment with an mGlu2 or mGlu3 NAM rapidly activated biophysically unique PFC pyramidal cell ensembles. Mechanistic studies revealed that mGlu2 and mGlu3 NAMs enhance thalamocortical transmission and inhibit long-term depression by mechanistically distinct presynaptic and postsynaptic actions. Consistent with these actions, systemic treatment with either NAM decreased passive coping and reversed anhedonia in two independent chronic stress models, suggesting that both mGlu2 and mGlu3 NAMs induce antidepressant-like effects through related but divergent mechanisms of action.
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