Dataset Information

Differential regulation of striatal motor behavior and related cellular responses by dopamine D2L and D2S isoforms.

ABSTRACT: The dopamine D2 receptor (D2R) is a major component of the dopamine system. D2R-mediated signaling in dopamine neurons is involved in the presynaptic regulation of dopamine levels. Postsynaptically, i.e., in striatal neurons, D2R signaling controls complex functions such as motor activity through regulation of cell firing and heterologous neurotransmitter release. The presence of two isoforms, D2L and D2S, which are generated by a mechanism of alternative splicing of the Drd2 gene, raises the question of whether both isoforms may equally control presynaptic and postsynaptic events. Here, we addressed this question by comparing behavioral and cellular responses of mice with the selective ablation of either D2L or D2S isoform. We establish that the presence of either D2L or D2S can support postsynaptic functions related to the control of motor activity in basal conditions. On the contrary, absence of D2S but not D2L prevents the inhibition of tyrosine hydroxylase phosphorylation and, thereby, of dopamine synthesis, supporting a major presynaptic role for D2S. Interestingly, boosting dopamine signaling in the striatum by acute cocaine administration reveals that absence of D2L, but not of D2S, strongly impairs the motor and cellular response to the drug, in a manner similar to the ablation of both isoforms. These results suggest that when the dopamine system is challenged, D2L signaling is required for the control of striatal circuits regulating motor activity. Thus, our findings show that D2L and D2S share similar functions in basal conditions but not in response to stimulation of the dopamine system.

SUBMITTER: Radl D

PROVIDER: S-EPMC5776825 | biostudies-other | 2018 Jan

REPOSITORIES: biostudies-other

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Differential regulation of striatal motor behavior and related cellular responses by dopamine D2L and D2S isoforms.

Radl Daniela D Chiacchiaretta Martina M Lewis Robert G RG Brami-Cherrier Karen K Arcuri Ludovico L Borrelli Emiliana E

Proceedings of the National Academy of Sciences of the United States of America 20171218 1

The dopamine D2 receptor (D2R) is a major component of the dopamine system. D2R-mediated signaling in dopamine neurons is involved in the presynaptic regulation of dopamine levels. Postsynaptically, i.e., in striatal neurons, D2R signaling controls complex functions such as motor activity through regulation of cell firing and heterologous neurotransmitter release. The presence of two isoforms, D2L and D2S, which are generated by a mechanism of alternative splicing of the <i>Drd2</i> gene, raises ...[more]

PMID: 29255027

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Project description:Dopamine transporter (DAT) imaging is an in vivo tool to assess presynaptic dopaminergic function in the clinical practices of Parkinson's disease (PD). Current clinical practices focused on qualitatively visual interpretation of DAT imaging, whereas quantitative analyses are potentially more helpful when monitoring the progression of PD. Previous cross-sectional studies indicated certain motor and non-motor features were associated with striatal DAT binding, whereas limited data were reported in terms of the longitudinal correlation between clinical features of PD with striatal DAT binding. The purpose of our study is to clarify current and longitudinal correlations between striatal DAT binding and clinical measures. A total of 352 untreated PD individuals and 167 healthy controls with complete baseline clinical measures and neuroimaging data were identified from the Parkinson's Progression and Markers Initiative (PPMI) database. Patients with PD underwent DAT imaging at the screening visit and following months 12, 24, and 48. Multiple linear regression models and linear mixed-effect models were respectively conducted to investigate the cross-sectional and longitudinal correlation between clinical characteristics and DAT binding. Associations between changes in clinical characteristics and changes in DAT binding were further evaluated and the Spearman rank correlation coefficients were reported. In the cross-sectional analysis, baseline striatal DAT binding was significantly associated with the Hoehn and Yahr scale, the Movement Disorder Society-Sponsored Revision of the Unified Parkinson Disease Rating Scale (MDS-UPDRS) scores, the rigidity scores, and the axial scores in PD individuals (false discovery rate [FDR]-adjusted p = 0.0017 for all above). Patients who developed freezing of gait had lower striatal DAT binding (FDR-adjusted p = 0.0161). Healthy controls who had higher tremor scores and suffered more severe olfactory dysfunction had lower striatal DAT binding (FDR-adjusted p = 0.0257 for all above). Longitudinal analysis indicated that baseline severity of rapid-eye-movement sleep behavior disorder was significantly associated with longitudinal striatal DAT binding in patients with PD (FDR-adjusted p = 0.0120). Furthermore, changes in MDS-UPDRS scores and the State-Trait Anxiety Inventory (STAI) scores demonstrated significant correlations with changes in striatal DAT binding over 4 years (p = 0.005 and p = 0.032, respectively). Our findings clarified quantitative associations between certain motor and non-motor features with current and future striatal dopamine binding, suggesting the feasibility of using DAT images as a progression predictive marker for PD. Further studies are needed to investigate correlations between different regional dopamine binding with specific clinical features.

Dataset Information

Differential regulation of striatal motor behavior and related cellular responses by dopamine D2L and D2S isoforms.

Publications

Differential regulation of striatal motor behavior and related cellular responses by dopamine D2L and D2S isoforms.

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