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

Metabotropic glutamate receptor 2 (mGlu ₂ ) attracts particular attention as a possible target for a new class of antipsychotics. However, the signaling pathways transducing the effects of mGlu ₂ in the brain remain poorly characterized. Here, we addressed this issue by identifying native mGlu ₂ interactome in mouse prefrontal cortex. Nanobody-based affinity purification and mass spectrometry identified 149 candidate mGlu ₂ partners, including the neurotrophin receptor TrkB. The later interaction was confirmed both in cultured cells and prefrontal cortex. mGlu ₂ activation triggers phosphorylation of TrkB on Tyr ⁸¹⁶ in primary cortical neurons and prefrontal cortex. Reciprocally, TrkB stimulation enhances mGlu ₂ -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 mGlu ₂ , which is key to the behavioral response to glutamatergic antipsychotics.