The Expression and Functionality of CB₁R-NMDAR Complexes Are Decreased in A Parkinson's Disease Model

One of the hallmarks of Parkinson's disease (PD) is the alteration in the expression and function of NMDA receptor (NMDAR) and cannabinoid receptor 1 (CB₁R). The presence of CB₁R-NMDAR complexes has been described in neuronal primary cultures. The activation of CB₁R in CB₁R-NMDAR complexes was suggested to counteract the detrimental NMDAR overactivation in an AD mice model. Thus, we aimed to explore the role of this receptor complex in PD. By using Bioluminescence Resonance Energy Transfer (BRET) assay, it was demonstrated that α-synuclein induces a reorganization of the CB₁R-NMDAR complex in transfected HEK-293T cells. Moreover, α-synuclein treatment induced a decrease in the cAMP and MAP kinase (MAPK) signaling of both CB₁R and NMDAR not only in transfected cells but also in neuronal primary cultures. Finally, the interaction between CB₁R and NMDAR was studied by Proximity Ligation Assay (PLA) in neuronal primary cultures, where it was observed that the expression of CB₁R-NMDAR complexes was decreased upon α-synuclein treatment. These results point to a role of CB₁R-NMDAR complexes as a new therapeutic target in Parkinson's disease.