Selective Manipulation of G-Protein γ7Subunit in Mice Provides New Insights into Striatal Control of Motor Behavior
Autor: | Janet D. Robishaw, Anna M Stauffer, Gloria Brunori, Oliver B Pelletier |
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Rok vydání: | 2021 |
Předmět: | |
Zdroj: | The Journal of Neuroscience. 41:9065-9081 |
ISSN: | 1529-2401 0270-6474 |
Popis: | Stimulatory coupling of dopamine D1(D1R) and adenosine A2Areceptors (A2AR) to adenylyl cyclase within the striatum is mediated through a specific Gαolfβ2γ7heterotrimer to ultimately modulate motor behaviors. To dissect the individual roles of the Gαolfβ2γ7heterotrimer in different populations of medium spiny neurons (MSNs), we produced and characterized conditional mouse models, in which theGng7gene was deleted in either the D1R- or A2AR/D2R-expressing MSNs. We show that conditional loss of γ7disrupts the cell type-specific assembly of the Gαolfβ2γ7heterotrimer, thereby identifying its circumscribed roles acting downstream of either the D1Rs or A2ARs in coordinating motor behaviors, includingin vivoresponses to psychostimulants. We reveal that Gαolfβ2γ7/cAMP signal in D1R-MSNs does not impact spontaneous and amphetamine-induced locomotor 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, Gαolfβ2γ7/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 Gαolfβ2γ7signaling 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 γ7protein in determining the cellular level, and hence, the function of the Gαolfβ2γ7heterotrimer in several disease states associated with dysfunctional striatal signaling.SIGNIFICANCE STATEMENTDysfunction 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 γ7subunit in distinct striatal neuronal subpopulations in mice, we demonstrate that the formation and function of the Gαolfβ2γ7heterotrimer, which represents the rate-limiting step for cAMP production in the striatum, is selectively disrupted. Furthermore, we reveal cell type-specific roles for Gαolfβ2γ7-mediated cAMP production in the control of spontaneous locomotion as well as behavioral and molecular responses to psychostimulants. Our findings identify the γ7protein as a novel therapeutic target for disease states associated with dysfunctional striatal cAMP signaling. |
Databáze: | OpenAIRE |
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