Selective Manipulation of G-Protein γ₇ Subunit in Mice Provides New Insights into Striatal Control of Motor Behavior

Stimulatory coupling of dopamine D₁ (D₁R) and adenosine A_2A receptors (A_2AR) to adenylyl cyclase within the striatum is mediated through a specific Gα_olfβ₂γ₇ heterotrimer to ultimately modulate motor behaviors. To dissect the individual roles of the Gα_olfβ₂γ₇ heterotrimer in different populations of medium spiny neurons (MSNs), we produced and characterized conditional mouse models, in which the Gng7 gene was deleted in either the D₁R- or A_2AR/D₂R-expressing MSNs. We show that conditional loss of γ₇ disrupts the cell type-specific assembly of the Gα_olfβ₂γ₇ heterotrimer, thereby identifying its circumscribed roles acting downstream of either the D₁Rs or A_2ARs in coordinating motor behaviors, including in vivo responses to psychostimulants. We reveal that Gα_olfβ₂γ₇/cAMP signal in D₁R-MSNs does not impact spontaneous and amphetamine-induced locomotor behaviors in male and female mice, while its loss in A_2AR/D₂R-MSNs results in a hyperlocomotor phenotype and enhanced locomotor response to amphetamine. Additionally, Gα_olfβ₂γ₇/cAMP signal in either D₁R- or A_2AR/D₂R-expressing MSNs is not required for the activation of PKA signaling by amphetamine. Finally, we show that Gα_olfβ₂γ₇ signaling acting downstream of D₁Rs 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 γ₇ protein in determining the cellular level, and hence, the function of the Gα_olfβ₂γ₇ heterotrimer in several disease states associated with dysfunctional striatal signaling.SIGNIFICANCE STATEMENT 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 γ₇ subunit in distinct striatal neuronal subpopulations in mice, we demonstrate that the formation and function of the Gα_olfβ₂γ₇ heterotrimer, which represents the rate-limiting step for cAMP production in the striatum, is selectively disrupted. Furthermore, we reveal cell type-specific roles for Gα_olfβ₂γ₇-mediated cAMP production in the control of spontaneous locomotion as well as behavioral and molecular responses to psychostimulants. Our findings identify the γ₇ protein as a novel therapeutic target for disease states associated with dysfunctional striatal cAMP signaling.