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/DYT25). This gene encodes the αolf subunit of the heterotrimeric Golf protein, which, with β2γ7 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 in motor behavior. To dissect the specific roles of Gαolf in the two main populations of SPNs, we generated and characterized mice in which Gnal was conditionally deleted in neurons expressing either D1 receptors (D1-SPNs) or A2A receptors (A2A-SPNs). Our results confirm the critical role of Gαolf in regulating adenylyl-cyclase 5 and its coupling with D1 and A2A receptors. Mice with a selective loss of Gαolf in D1-SPNs show nocturnal hyperactivity, deficits in motor performances, but no overt abnormal movements or generalized motor disability. Our experiments also reveal that Gαolf in D1-SPNs is required locomotor responses induced by some, but not all, D1 agonists or psychostimulants. Selective loss of Gαolf in A2A-SPNs does not affect motor abilities or learning but strikingly increases spontaneous locomotor activity. Hyperactivity is not further enhanced by psychostimulant drugs (cocaine, D-amphetamine, methylphenidate) or a selective A2 agonist, KW6002, but is paradoxically reduced by caffeine. Our study identifies specific roles of Gαolf downstream of D1 and A2A receptors in the control of motor behavior and drug responses, highlighting their respective individual contribution in dysfunctional striatal signaling, including dystonia.