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Competitive regulation of synaptic Ca2+ influx by D2 dopamine and A2A adenosine receptors

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Abstract

Striatal D2-type dopamine receptors (D2Rs) have been implicated in the pathophysiology of neuropsychiatric disorders, including Parkinson's disease and schizophrenia. Although these receptors regulate striatal synaptic plasticity, the mechanisms underlying dopaminergic modulation of glutamatergic synapses are unclear. We combined optogenetics, two-photon microscopy and glutamate uncaging to examine D2R-dependent modulation of glutamatergic synaptic transmission in mouse striatopallidal neurons. We found that D2R activation reduces corticostriatal glutamate release and attenuates both synaptic- and action potential–evoked Ca2+ influx into dendritic spines by approximately 50%. Modulation of Ca2+ signaling was mediated by a protein kinase A (PKA)-dependent regulation of Ca2+ entry through NMDA-type glutamate receptors that was inhibited by D2Rs and enhanced by activation of 2A-type adenosine receptors (A2ARs). D2Rs also produced a PKA- and A2AR-independent reduction in Ca2+ influx through R-type voltage-gated Ca2+ channels. These findings reveal that dopamine regulates spine Ca2+ by multiple pathways and that competitive modulation of PKA controls NMDAR-mediated Ca2+ signaling in the striatum.

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Figure 1: Modulation of corticostriatal synaptic responses in striatopallidal MSNs by D2Rs.
Figure 2: D2R modulation of uncaging-evoked Ca2+ transients in active spines.
Figure 3: Multiple Ca2+ sources contribute to synaptic Ca2+ signaling.
Figure 4: Activation of D2Rs modulates NMDAR-mediated, but not nonNMDAR-mediated, synaptic responses.
Figure 5: Activation of D2Rs modulates R-type VGCCs.
Figure 6: Voltage-steps reveal L-type Ca2+ channels in MSN spines.
Figure 7: Push-pull modulation of NMDARs by D2Rs and A2ARs is dependent on PKA activity.
Figure 8: Modulation of VGCCs by D2Rs is independent of A2AR and PKA activity.

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  • 11 July 2010

    The sizing of Figure 6 has been modified in the print, PDF and HTML versions of this article.

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Acknowledgements

The authors thank members of the Sabatini laboratory and J.A. Cardin for helpful comments during the preparation of this manuscript. We thank K. Deisseroth and V. Gradinaru for assistance with the ChR2 experiments. The work was funded by grants from the Parkinson's Disease Foundation (Postdoctoral Fellowship) and the National Institute of Neurological Disorders and Stroke (NS063663) to M.J.H. and grants from the National Institute of Neurological Disorders and Stroke (NS046579) and the National Alliance for Research on Schizophrenia and Depression (Independent Investigator Award) to B.L.S.

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M.J.H. conducted the experiments and data analysis. M.J.H. and B.L.S. designed the experiments and wrote the manuscript.

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Correspondence to Bernardo L Sabatini.

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Higley, M., Sabatini, B. Competitive regulation of synaptic Ca2+ influx by D2 dopamine and A2A adenosine receptors. Nat Neurosci 13, 958–966 (2010). https://doi.org/10.1038/nn.2592

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