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 α_olf subunit of the heterotrimeric G_olf 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 Gα_olf 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 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 show nocturnal hyperactivity, deficits in motor performances, but no overt abnormal movements or generalized motor disability. Our experiments also reveal that Gα_olf in D1-SPNs is required locomotor responses induced by some, but not all, D1 agonists or psychostimulants. Selective loss of Gα_olf 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 Gα_olf 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.