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TrkB receptor interacts with mGlu₂ receptor and mediates antipsychotic-like effects of mGlu₂ receptor activation in the mouse.

ABSTRACT: Metabotropic glutamate receptor 2 (mGlu₂) attracts particular attention as a possible target for a new class of antipsychotics. However, the signaling pathways transducing the effects of mGlu₂ in the brain remain poorly characterized. Here, we addressed this issue by identifying native mGlu₂ interactome in mouse prefrontal cortex. Nanobody-based affinity purification and mass spectrometry identified 149 candidate mGlu₂ partners, including the neurotrophin receptor TrkB. The later interaction was confirmed both in cultured cells and prefrontal cortex. mGlu₂ activation triggers phosphorylation of TrkB on Tyr⁸¹⁶ in primary cortical neurons and prefrontal cortex. Reciprocally, TrkB stimulation enhances mGlu₂-operated G_i/o protein activation. Furthermore, TrkB inhibition prevents the rescue of behavioral deficits by glutamatergic antipsychotics in phencyclidine-treated mice. Collectively, these results reveal a cross-talk between TrkB and mGlu₂, which is key to the behavioral response to glutamatergic antipsychotics.

SUBMITTER: Philibert CE

PROVIDER: S-EPMC10816717 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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TrkB receptor interacts with mGlu2 receptor and mediates antipsychotic-like effects of mGlu2 receptor activation in the mouse.

Philibert Clémentine Eva CE Disdier Candice C Lafon Pierre-André PA Bouyssou Alexandre A Oosterlaken Mathieu M Galant Sonya S Pizzoccaro Anne A Tuduri Pola P Ster Jeanne J Liu Jianfeng J Kniazeff Julie J Pin Jean-Philippe JP Rondard Philippe P Marin Philippe P Vandermoere Franck F

Science advances 20240126 4

Metabotropic glutamate receptor 2 (mGlu2) attracts particular attention as a possible target for a new class of antipsychotics. However, the signaling pathways transducing the effects of mGlu2 in the brain remain poorly characterized. Here, we addressed this issue by identifying native mGlu2 interactome in mouse prefrontal cortex. Nanobody-based affinity purification and mass spectrometry identified 149 candidate mGlu2 partners, including the neurotrop ...[more]

PMID: 38277461

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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.

Project description:The generation of muscarinic acetylcholine receptor (mAChR) subtype-selective compounds has been challenging, requiring use of nonpharmacological approaches, such as genetically engineered animals, to deepen our understanding of the potential that members of the muscarinic receptor subtype family hold as therapeutic drug targets. The muscarinic receptor agonist 'BuTAC' was previously shown to exhibit efficacy in animal models of psychosis, although the particular receptor subtype(s) responsible for such activity was unclear. Here, we evaluate the in vitro functional agonist and antagonist activity of BuTAC using an assay that provides a direct measure of G protein activation. In addition, we employ the conditioned avoidance response paradigm, an in vivo model predictive of antipsychotic activity, and mouse genetic deletion models to investigate which presynaptic mAChR subtype mediates the antipsychotic-like effects of BuTAC. Our results show that, in vitro, BuTAC acts as a full agonist at the M2AChR and a partial agonist at the M1 and M4 receptors, with full antagonist activity at M3- and M5AChRs. In the mouse conditioned avoidance response (CAR) assay, BuTAC exhibits an atypical antipsychotic-like profile by selectively decreasing avoidance responses at doses that do not induce escape failures. CAR results using M2(-/-), M4(-/-), and M2/M4 (M2/M4(-/-)) mice found that the effects of BuTAC were near completely lost in M2/M4(-/-) double-knockout mice and potency of BuTAC was right-shifted in M4(-/-) as compared with wild-type and M2(-/-) mice. The M2/M4(-/-) mice showed no altered sensitivity to the antipsychotic effects of either haloperidol or clozapine, suggesting that these compounds mediate their actions in CAR via a non-mAChR-mediated mechanism. These data support a role for the M4AChR subtype in mediating the antipsychotic-like activity of BuTAC and implicate M4AChR agonism as a potential novel therapeutic mechanism for ameliorating symptoms associated with schizophrenia.

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TrkB receptor interacts with mGlu₂ receptor and mediates antipsychotic-like effects of mGlu₂ receptor activation in the mouse.

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TrkB receptor interacts with mGlu<sub>2</sub> receptor and mediates antipsychotic-like effects of mGlu<sub>2</sub> receptor activation in the mouse.

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TrkB receptor interacts with mGlu2 receptor and mediates antipsychotic-like effects of mGlu2 receptor activation in the mouse.

Publications

TrkB receptor interacts with mGlu&lt;sub&gt;2&lt;/sub&gt; receptor and mediates antipsychotic-like effects of mGlu&lt;sub&gt;2&lt;/sub&gt; receptor activation in the mouse.

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OmicsDI is part of the ELIXIR infrastructure

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TrkB receptor interacts with mGlu₂ receptor and mediates antipsychotic-like effects of mGlu₂ receptor activation in the mouse.

TrkB receptor interacts with mGlu<sub>2</sub> receptor and mediates antipsychotic-like effects of mGlu<sub>2</sub> receptor activation in the mouse.