Neuron
Volume 105, Issue 1, 8 January 2020, Pages 46-59.e3
Journal home page for Neuron

Article
mGlu2 and mGlu3 Negative Allosteric Modulators Divergently Enhance Thalamocortical Transmission and Exert Rapid Antidepressant-like Effects

https://doi.org/10.1016/j.neuron.2019.09.044Get rights and content
Under an Elsevier user license
open archive

Highlights

  • mGlu2 and mGlu3 negative allosteric modulators (NAMs) stimulate prefrontal cortex

  • mGlu2 regulates thalamocortical glutamate release probability

  • mGlu3 directs prefrontal cortex postsynaptic plasticity

  • mGlu2 and mGlu3 NAMs independently decrease passive coping and reverse anhedonia

Summary

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.

Keywords

metabotropic glutamate receptor
mGlu receptor
prefrontal cortex
thalamus
synaptic plasticity
neuronal ensembles
major depressive disorder
chronic stress
anhedonia
antidepressant

Cited by (0)

7

Twitter: @mejoffe

8

Lead Contact