Optical Control of Drd2 Reveals a New Role of Drd2 for Motor Function in the Lgp Excitatory Neurons

Dopaminergic pathways play crucial roles in motor function via the coordination of subtypes of dopamine receptors (DRDs), thus functional imbalance between different DRD subtypes can lead to motor dysfunctions and Parkinson’s disease. However, it is challenging to investigate the individual functions of each DRD subtype in the brain because of the complexity of dopaminergic circuits and the lack of advanced biotechnology. Here, we developed OptoDRD2, a chimeric receptor composed of the light-responsive part of rhodopsin and the intracellular signaling part of DRD2. Upon illumination of blue light, OptoDRD2 successfully induced DRD2-specific signaling pathways such as the cAMP decrease and the phosphorylation of ERK and pDARPP-32. To explore the unknown roles of DRD2 in glutamatergic cell populations of basal ganglia circuitry, OptoDRD2 was expressed in the excitatory neurons at the lateral globus pallidus (LGP) region of the mouse brain. The optogenetic stimulation of the OptoDRD2 can control a wide range of movement parameters in an intensity-dependent manner, such as velocity, elevated velocity epoch length, average acceleration. These results suggest hitherto a novel role for DRD2 facilitating motor output in the excitatory neurons in LGP region of the brain. Therefore, OptoDRD2 can be broadly applied to investigate specific functions of DRD2 during dopaminergic transmission in different cell types and regions of the brain.