2. Academic Validation
  3. mGlu2 and mGlu3 Negative Allosteric Modulators Divergently Enhance Thalamocortical Transmission and Exert Rapid Antidepressant-like Effects

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

  • Neuron. 2020 Jan 8;105(1):46-59.e3. doi: 10.1016/j.neuron.2019.09.044.
Max E Joffe 1,  Chiaki I Santiago 2,  Kendra H Oliver 3,  James Maksymetz 4,  Nicholas A Harris 5,  Julie L Engers 6,  Craig W Lindsley 7,  Danny G Winder 8,  P Jeffrey Conn 9
Affiliations

Affiliations

  • 1 Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Nashville, TN 37232, USA; Vanderbilt Center for Addiction Research, Nashville, TN 37232, USA. Electronic address: [email protected].
  • 2 Vanderbilt Center for Neuroscience Drug Discovery, Nashville, TN 37232, USA; Vanderbilt University, Nashville, TN 37232, USA.
  • 3 Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA.
  • 4 Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Nashville, TN 37232, USA.
  • 5 Vanderbilt Center for Addiction Research, Nashville, TN 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
  • 6 Vanderbilt Center for Neuroscience Drug Discovery, Nashville, TN 37232, USA.
  • 7 Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Nashville, TN 37232, USA; Vanderbilt Center for Addiction Research, Nashville, TN 37232, USA; Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
  • 8 Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Addiction Research, Nashville, TN 37232, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA.
  • 9 Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Nashville, TN 37232, USA; Vanderbilt Center for Addiction Research, Nashville, TN 37232, USA. Electronic address: [email protected].
PMID: 31735403 DOI: 10.1016/j.neuron.2019.09.044
Abstract

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

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

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