Selective Manipulation of G-Protein γ Subunit in Mice Provides New Insights into Striatal Control of Motor Behavior.

Stimulatory coupling of dopamine D (DR) and adenosine A receptors (AR) to adenylyl cyclase within the striatum is mediated through a specific Gαβγ heterotrimer to ultimately modulate motor behaviors. To dissect the individual roles of the Gαβγ heterotrimer in different populations of medium spiny neurons (MSNs), we produced and characterized conditional mouse models, in which the gene was deleted in either the DR- or AR/DR-expressing MSNs. We show that conditional loss of γ disrupts the cell type-specific assembly of the Gαβγ heterotrimer, thereby identifying its circumscribed roles acting downstream of either the DRs or ARs in coordinating motor behaviors, including responses to psychostimulants. We reveal that Gαβγ/cAMP signal in DR-MSNs does not impact spontaneous and amphetamine-induced locomotor behaviors in male and female mice, while its loss in AR/DR-MSNs results in a hyperlocomotor phenotype and enhanced locomotor response to amphetamine. Additionally, Gαβγ/cAMP signal in either DR- or AR/DR-expressing MSNs is not required for the activation of PKA signaling by amphetamine. Finally, we show that Gαβγ signaling acting downstream of DRs is selectively implicated in the acute locomotor-enhancing effects of morphine. Collectively, these results support the general notion that receptors use specific Gαβγ proteins to direct the fidelity of downstream signaling pathways and to elicit a diverse repertoire of cellular functions. Specifically, these findings highlight the critical role for the γ protein in determining the cellular level, and hence, the function of the Gαβγ heterotrimer in several disease states associated with dysfunctional striatal signaling. Dysfunction or imbalance of cAMP signaling in the striatum has been linked to several neurologic and neuropsychiatric disorders, including Parkinson's disease, dystonia, schizophrenia, and drug addiction. By genetically targeting the γ subunit in distinct striatal neuronal subpopulations in mice, we demonstrate that the formation and function of the Gαβγ heterotrimer, which represents the rate-limiting step for cAMP production in the striatum, is selectively disrupted. Furthermore, we reveal cell type-specific roles for Gαβγ-mediated cAMP production in the control of spontaneous locomotion as well as behavioral and molecular responses to psychostimulants. Our findings identify the γ protein as a novel therapeutic target for disease states associated with dysfunctional striatal cAMP signaling.