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

Metabotropic glutamate receptor 2 (mGlu) attracts particular attention as a possible target for a new class of antipsychotics. However, the signaling pathways transducing the effects of mGlu in the brain remain poorly characterized. Here, we addressed this issue by identifying native mGlu interactome in mouse prefrontal cortex. Nanobody-based affinity purification and mass spectrometry identified 149 candidate mGlu partners, including the neurotrophin receptor TrkB. The later interaction was confirmed both in cultured cells and prefrontal cortex. mGlu activation triggers phosphorylation of TrkB on Tyr in primary cortical neurons and prefrontal cortex. Reciprocally, TrkB stimulation enhances mGlu-operated G 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 mGlu, which is key to the behavioral response to glutamatergic antipsychotics.