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

Abstract

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.

Dopamine Receptor Subtypes, Physiology and Pharmacology: New Ligands and Concepts in Schizophrenia

“…D2 antagonism is still recognized as a main stay of SCZ therapy and the D2 receptor is considered to be directly or indirectly responsible for the efficacy of the majority of typical and atypical antipsychotics. This is coherent with the general observation of a main role of DA control of cortico-striatal synchronization of D2-MSN neurons (via D2-GPRIN AKT) ( Karadurmus et al., 2019 ). The tetra complex A2A-D2 receptors (plus AC5) is really central to multiple effects of both adenosine and DR ligands in the striatal region ( Ferre et al., 2018 ; Bonifazi et al., 2019 ).…”

Drug addiction: from bench to bedside

“…Thus, we tested the cocaine acute effect and locomotor sensitization and observed a decrease in cocaine-induced hyperlocomotion after inactivation of GPRIN3 using a CRISP/Cas9 approach. The significant increase in distal branching in GPRIN3 D2R-MSNs KD corroborates our hypothesis that the lack of GPRIN3 induces a ‘presensitization process’, able to change the targets of cocaine and therefore altering its effects [ 149 ]. Finally, we provide the first evidence that GPRIN3 partners with D2R in the striatum and modulates cocaine-induced behaviours [ 149 ].…”

“…Our hypothesis is that, in line with the previously discussed in vivo optogenetic induced LTD, this impairment could be a key factor for the significant decrease in sensitization to psychostimulants [ 87 , 103 , 148 ]. Actually, it seems that placing neurons in a state of ‘presensitization’ is able to prevent drug-induced sensitization itself [ 148 , 149 ]. Our group is now trying to understand what are the cellular and molecular pathways directly altered by Maged1 inactivation and responsible for this strong anti-addictive drug phenotype.…”

“…This selected gene approach is of great interest in refining our knowledge of pathways hijacked by addictive drugs. Using cell sorting of D1R MSNs and D2R MSNs as described previously [ 151 ], our group also identified the G-protein-regulated inducer of neurite outgrowth 3 (GPRIN3) in both MSN populations but strikingly more expressed in D2R MSNs [ 149 ]. The GPRIN family (GPRIN1, GPRIN2 and GPRIN3) are Gαi/o-regulated proteins suggested to intermediate the communication between GPCRs and the sequential intracellular target [ 152 ].…”

Overlapping variants in the blood, tissues and cell lines for patients with intracranial meningiomas are predominant in stem cell-related genes

“…The mouse homologue to GPRIN2 was found to be enriched in neural growth cone membranes of embryonic mouse brain cells collected at day 17 of embryogenesis, and has shown to be important for the control of neurons growth [ 45 , 46 ]. G protein regulated inducers of neurite outgrowth proteins function as intermediates for the communication between G protein-coupled receptors and sequential intracellular targets [ 47 ]. GPRIN2 has been observed to bind to Gαo-protein-activating Cdc42, resulting in changes to its cellular morphology [ 48 ].…”