Dataset Information

MGlu₂ and mGlu₃ Negative Allosteric Modulators Divergently Enhance Thalamocortical Transmission and Exert Rapid Antidepressant-like Effects.

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.

SUBMITTER: Joffe ME

PROVIDER: S-EPMC6952546 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Joffe Max E ME Santiago Chiaki I CI Oliver Kendra H KH Maksymetz James J Harris Nicholas A NA Engers Julie L JL Lindsley Craig W CW Winder Danny G DG Conn P Jeffrey PJ

Neuron 20191114 1

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 mG ...[more]

PMID: 31735403

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Project description:Metabotropic glutamate (mGlu) receptors are promising targets for the treatment of affective disorders and alcohol use disorder (AUD). Nonspecific ligands for Group II (mGlu2 and mGlu3) mGlu receptors have demonstrated consistent therapeutic potential for affective disorders in preclinical models. Disentangling the specific roles of mGlu2 versus mGlu3 receptors in these effects has persisted as a major challenge, in part due to pharmacological limitations. However, the recent development of highly specific allosteric modulators for both mGlu2 and mGlu3 receptors have enabled straightforward and rigorous investigations into the specific function of each receptor. Here, we review recent experiments using these compounds that have demonstrated both similar and distinct receptor functions in behavioral, molecular, and electrophysiological measures associated with basal function and preclinical models of affective disorders. Studies using these selective drugs have demonstrated that mGlu2 is the predominant receptor subclass involved in presynaptic neurotransmitter release in prefrontal cortex. By contrast, the activation of postsynaptic mGlu3 receptors induces a cascade of cellular changes that results in AMPA receptor internalization, producing long-term depression and diminishing excitatory drive. Acute stress decreases the mGlu3 receptor function and dynamically alters transcript expression for both mGlu2 (Grm2) and mGlu3 (Grm3) receptors in brain areas involved in reward and stress. Accordingly, both mGlu2 and mGlu3 negative allosteric modulators show acute antidepressant-like effects and potential prophylactic effects against acute and traumatic stressors. The wide array of effects displayed by these new allosteric modulators of mGlu2 and mGlu3 receptors suggest that these drugs may act through improving endophenotypes of symptoms observed across several neuropsychiatric disorders. Therefore, recently developed allosteric modulators selective for mGlu2 or mGlu3 receptors show promise as potential therapeutics for affective disorders and AUD.

Dataset Information

MGlu₂ and mGlu₃ Negative Allosteric Modulators Divergently Enhance Thalamocortical Transmission and Exert Rapid Antidepressant-like Effects.

Publications

mGlu<sub>2</sub> and mGlu<sub>3</sub> Negative Allosteric Modulators Divergently Enhance Thalamocortical Transmission and Exert Rapid Antidepressant-like Effects.

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Dataset Information

MGlu2 and mGlu3 Negative Allosteric Modulators Divergently Enhance Thalamocortical Transmission and Exert Rapid Antidepressant-like Effects.

Publications

mGlu<sub>2</sub> and mGlu<sub>3</sub> Negative Allosteric Modulators Divergently Enhance Thalamocortical Transmission and Exert Rapid Antidepressant-like Effects.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

MGlu₂ and mGlu₃ Negative Allosteric Modulators Divergently Enhance Thalamocortical Transmission and Exert Rapid Antidepressant-like Effects.