Characterization of mice with cell type-specific Gnal loss of function provides insights on GNAL -linked dystonia

Isolated dystonia can be caused by loss-of-function mutations in the GNAL gene (DYT-GNAL). This gene encodes the α _olf heterotrimeric G protein subunit, which, together with β ₂ γ ₇ subunits, mediates the stimulatory coupling of dopamine D1 and adenosine A2A receptors to adenylyl-cyclase. These receptors are expressed in distinct striatal projection neurons (SPNs) with complementary functions on motor behavior. To dissect the specific roles of Gα _olf in each subpopulation of SPNs, we generated and characterized mouse models in which Gnal was conditionally deleted in neurons expressing either D1 receptors (D1-SPNs) or A2A receptors (A2A-SPNs). Our results confirmed the critical role of Gα _olf in regulating adenylyl-cyclase 5 and its coupling with D1 and A2A receptors. Mice with a selective loss of Gα _olf in D1-SPNs showed nocturnal hyperactivity, deficits in motor performances, but no overt abnormal movements or generalized motor disability. Our experiments also revealed that Gα _olf in D1-SPNs is not systematically required for locomotor responses induced by D1 agonists or psychostimulants. Selective loss of Gα _olf in A2A-SPNs did not affect motor abilities nor learning. However, this loss strikingly increased spontaneous locomotor activity that was not further enhanced by psychostimulant drugs (cocaine, D-amphetamine, methylphenidate) or a selective A2 agonist, KW6002, and was paradoxically reduced by caffeine Our study identified specific roles of Gα _olf downstream of D1 and A2A receptors in the control of motor behavior and drug responses, highlighting their respective individual contribution in diseases associated with dysfunctional striatal signaling, including dystonia.