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mGlu 2 and mGlu 3 Negative Allosteric Modulators Divergently Potentiate Thalamocortical Transmission and Exert Rapid Antidepressant-Like Effects

45 Pages Posted: 6 May 2019 Sneak Peek Status: Review Complete

See all articles by Max E. Joffe

Max E. Joffe

Vanderbilt University - Department of Pharmacology

Chiaki I. Santiago

Vanderbilt University - Vanderbilt Center for Neuroscience Drug Discovery

Kendra H. Oliver

Vanderbilt University - Department of Pharmacology

Nicholas A. Harris

Vanderbilt University - Vanderbilt Center for Addiction Research

Julie L. Engers

Vanderbilt University - Vanderbilt Center for Neuroscience Drug Discovery

Craig W. Lindsley

Vanderbilt University - Department of Pharmacology

Danny G. Winder

Vanderbilt University - Department of Pharmacology

Peter Jeffrey Conn

Vanderbilt University - Department of Pharmacology

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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 that label NAM-activated neuronal ensembles, 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 but do so 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, prefrontal cortex, thalamus, synaptic plasticity, neuronal ensembles, major depressive disorder, chronic stress, antidepressant

Suggested Citation

Joffe, Max E. and Santiago, Chiaki I. and Oliver, Kendra H. and Harris, Nicholas A. and Engers, Julie L. and Lindsley, Craig W. and Winder, Danny G. and Conn, Peter Jeffrey, mGlu 2 and mGlu 3 Negative Allosteric Modulators Divergently Potentiate Thalamocortical Transmission and Exert Rapid Antidepressant-Like Effects (May 2, 2019). NEURON-D-19-00611. Available at SSRN: https://ssrn.com/abstract=3381951 or http://dx.doi.org/10.2139/ssrn.3381951
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Max E. Joffe

Vanderbilt University - Department of Pharmacology ( email )

United States

Chiaki I. Santiago

Vanderbilt University - Vanderbilt Center for Neuroscience Drug Discovery ( email )

United States

Kendra H. Oliver

Vanderbilt University - Department of Pharmacology ( email )

United States

Nicholas A. Harris

Vanderbilt University - Vanderbilt Center for Addiction Research ( email )

United States

Julie L. Engers

Vanderbilt University - Vanderbilt Center for Neuroscience Drug Discovery ( email )

United States

Craig W. Lindsley

Vanderbilt University - Department of Pharmacology ( email )

United States

Danny G. Winder

Vanderbilt University - Department of Pharmacology ( email )

United States

Peter Jeffrey Conn (Contact Author)

Vanderbilt University - Department of Pharmacology ( email )

United States

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