Selective Manipulation of G-Protein c7 Subunit in Mice Provides New Insights into Striatal Control of Motor Behavior

Stimulatory coupling of dopamine D1 (D1R) and adenosine A2A receptors (A2AR) to adenylyl cyclase within the striatum is mediated through a specific Gaolfb2c7 heterotrimer to ultimately modulate motor behaviors. To dissect the individual roles of the Gaolfb2c7 heterotrimer in different populations of medium spiny neurons (MSNs), we produced and characterized condi-tional mouse models, in which the Gng7 gene was deleted in either the D1R-or A2AR/D2R-expressing MSNs. We show that conditional loss of c7 disrupts the cell type-specific assembly of the Gaolfb2c7 heterotrimer, thereby identifying its circumscribed roles acting downstream of either the D1Rs or A2ARs in coordinating motor behaviors, including in vivo responses to psychosti-mulants. We reveal that Gaolfb2c7/cAMP signal in D1R-MSNs does not impact spontaneous and amphetamine-induced locomo-tor behaviors in male and female mice, while its loss in A2AR/D2R-MSNs results in a hyperlocomotor phenotype and enhanced locomotor response to amphetamine. Additionally, Gaolfb2c7/cAMP signal in either D1R-or A2AR/D2R-expressing MSNs is not required for the activation of PKA signaling by amphetamine. Finally, we show that Gaolfb2c7 signaling acting downstream of D1Rs is selectively implicated in the acute locomotor-enhancing effects of morphine. Collectively, these results support the gen-eral notion that receptors use specific Gabc 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 c7 protein in determining the cellular level, and hence, the function of the Gaolfb2c7 heterotrimer in several disease states associated with dysfunctional striatal signaling.

Automated summary

The study reveals the importance of Gaolfb2c7/cAMP signaling in specific populations of MSNs in regulating motor behaviors, acting through D1R and A2AR to coordinate behavior. Additionally, the loss of Gaolfb2c7 in A2AR/D2R-MSNs leads to a hyperlocomotor phenotype and enhanced locomotor response to amphetamine.