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

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.