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Endocytosis following dopamine D2 receptor activation is critical for neuronal activity and dendritic spine formation via Rabex-5/PDGFRβ signaling in striatopallidal medium spiny neurons

Molecular Psychiatry volume 22, pages 1205–1222 (2017)Cite this article

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Abstract

Aberrant dopamine D2 receptor (D2R) activity is associated with neuropsychiatric disorders, making those receptors targets for antipsychotic drugs. Here, we report that novel signaling through the intracellularly localized D2R long isoform (D2LR) elicits extracellular signal-regulated kinase (ERK) activation and dendritic spine formation through Rabex-5/platelet-derived growth factor receptor-β (PDGFRβ)-mediated endocytosis in mouse striatum. We found that D2LR directly binds to and activates Rabex-5, promoting early-endosome formation. Endosomes containing D2LR and PDGFRβ are then transported to the Golgi apparatus, where those complexes trigger Gαi3-mediated ERK signaling. Loss of intracellular D2LR-mediated ERK activation decreased neuronal activity and dendritic spine density in striatopallidal medium spiny neurons (MSNs). In addition, dendritic spine density in striatopallidal MSNs significantly increased following treatment of striatal slices from wild-type mice with quinpirole, a D2R agonist, but those changes were lacking in D2LR knockout mice. Moreover, intracellular D2LR signaling mediated effects of a typical antipsychotic drug, haloperidol, in inducing catalepsy behavior. Taken together, intracellular D2LR signaling through Rabex-5/PDGFRβ is critical for ERK activation, dendritic spine formation and neuronal activity in striatopallidal MSNs of mice.

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Acknowledgements

We thank Dr Mitsunori Fukuda (Tohoku University, Sendai, Japan) for kindly providing Rabex-5, Rabex-5-D313A, Rabex-5C, Rabex-5C-D313A and Rabex-5 shRNA plasmids; Dr Wei-Xing Zong (Stony Brook University, Stony Brook, NY, USA) for kindly providing Rab5(WT), Rab5(S34N) and Rab5(Q79L) plasmids; Dr Guangpu Li (University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA) for kindly providing GST-R5BD; and Dr Jonathan A. Javitch (Columbia University, New York, NY, USA) for kindly providing D2LR-RLuc8, D2SR-RLuc8, Gαi1-mVenus, Gαi2-mVenus and Gαi3-mVenus plasmids. This work was supported by Grants-in-Aid for Scientific Research on Innovative Area “Foundation of Synapse and Neurocircuit Pathology” from the Ministry of Education, Culture, Sports, Science and Technology, Japan (25110705 and 25460090 to NS) and (24102505 and 25293124 to KF).

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Authors and Affiliations

  1. Department of Biofunctional Analysis Laboratory of Molecular Biology, Gifu Pharmaceutical University, Gifu, Japan

    N Shioda

  2. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan

    Y Yabuki & K Fukunaga

  3. Department of Pharmacology, Beckman Institute, University of Illinois, Urbana, IL, USA

    Y Wang

  4. Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo, Japan

    M Uchigashima & M Watanabe

  5. Department of Research and Drug Discovery, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan

    T Hikida

  6. Department of Comparative and Experimental Medicine, Brain Research Institute, Niigata University, Niigata, Japan

    T Sasaoka

  7. Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan

    H Mori

  8. Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama, Japan

    M Sasahara

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  1. N Shioda
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Shioda, N., Yabuki, Y., Wang, Y. et al. Endocytosis following dopamine D2 receptor activation is critical for neuronal activity and dendritic spine formation via Rabex-5/PDGFRβ signaling in striatopallidal medium spiny neurons. Mol Psychiatry 22, 1205–1222 (2017). https://doi.org/10.1038/mp.2016.200

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