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The regulation of the striatum by the GPCR signaling through neuromodulators is essential for its physiology and physiopathology, so it is necessary to know all the compounds of these pathways. In this study, we identified a new important partner of the dopaminergic pathway: GPRIN3 (a member of the GPRIN family). GPRIN3 is highly expressed in the striatum but with undefined function. Cell sorting of medium spiny neurons (MSNs) in indirect MSNs and direct MSNs indicated the presence of the GPRIN3 gene in both populations with a preferential expression in indirect MSNs. This led us to generate GPRIN3 KO mice by CRISPR/Cas9 and test male animals to access possible alterations in morphological, electrophysiological, and behavioral parameters following its absence. 3D reconstruction analysis of MSNs revealed increased neuronal arborization in GPRIN3 KO and modified passive and active electrophysiological properties. These cellular alterations were coupled with increased motivation and cocaine-induced hyperlocomotion. Additionally, using a specific indirect MSN knockdown, we showed a preferential role for GPRIN3 in indirect MSNs related to the D 2 R signaling. Together, these results show that GPRIN3 is a mediator of D 2 R function in the striatum playing a major role in striatal physiology. SIGNIFICANCE STATEMENT The striatum is the main input of the basal ganglia processing information from different brain regions through the combined actions of direct pathway neurons and indirect pathway neurons. Both neuronal populations are defined by the expression of dopamine D 1 R or D 2 R GPCRs, respectively. How these neurons signal to the respective G-protein is still debatable. Here we identified GPRIN3 as a putative selective controller of D 2 R function in the striatum playing a critical role in striatal-associated behaviors and cellular functions. This study represents the identification of a new target to tackle striatal dysfunction associated with the D 2 R, such as schizophrenia, Parkinson's disease, and drug addiction.

GPRIN3 Controls Neuronal Excitability, Morphology, and Striatal-Dependent Behaviors in the Indirect Pathway of the Striatum