Article | Published:

Identification of a Vav2-dependent mechanism for GDNF/Ret control of mesolimbic DAT trafficking

Nature Neuroscience volume 18, pages 10841093 (2015) | Download Citation

Abstract

Dopamine (DA) homeostasis is essential for a variety of brain activities. Dopamine transporter (DAT)-mediated DA reuptake is one of the most critical mechanisms for normal DA homeostasis. However, the molecular mechanisms underlying the regulation of DAT activity in the brain remain poorly understood. Here we show that the Rho-family guanine nucleotide exchange factor protein Vav2 is required for DAT cell surface expression and transporter activity modulated by glial cell line–derived neurotrophic factor (GDNF) and its cognate receptor Ret. Mice deficient in either Vav2 or Ret displayed elevated DAT activity, which was accompanied by an increase in intracellular DA selectively in the nucleus accumbens. Vav2−/− mice exposed to cocaine showed reduced DAT activity and diminished behavioral cocaine response. Our data demonstrate that Vav2 is a determinant of DAT trafficking in vivo and contributes to the maintenance of DA homeostasis in limbic DA neuron terminals.

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Acknowledgements

We thank X.C. Zhen (Soochow University) for providing the DAT cDNA, C. He (Second Military Medical University, China) for human RET cDNA, H.L. Hu and Z.L. Qiu (Institute of Neuroscience, Chinese Academy of Sciences) for the AAV virus constructs, L.P. Cheng (Institute of Neuroscience, Chinese Academy of Sciences) for the Ret mutant mice and the Riken BioResource Center for the TH-GFP transgenic mice. We also thank the Optical Imaging Center of the Institute of Neuroscience, Chinese Academy of Sciences, for technical support in confocal microscopy and the Behavioral Core of ION for providing assistance. This work was supported by grants from the National Key Basic Research Program of China (2015CB553500, 2011CB504102), Natural Science Foundation of China (31123002, 31321091 and 30621130075), Beijing Institute for Brain Disorders (BIBD-PXM2013_014226_07_000084) and Strategic Priority Research Program (B) of the Chinese Academy of Sciences (XDB01020300). X.R.B.'s work has been funded by the Spanish Ministry of Economy and Competitiveness (SAF2009-07172, SAF2012-3171, RD06/0020/0001 and RD12/0036/0002), the Castilla-León Autonomous Government (CSI101U13) and Spanish Association of Science Communication.

Author information

Author notes

    • Shuyong Zhu

    Present address: Institute of Virology, Hannover Medical School, Hannover, Germany.

    • Shuyong Zhu
    • , Chengjiang Zhao
    •  & Yingying Wu

    These authors contributed equally to this work.

Affiliations

  1. Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences Center for Excellence in Brain Science, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

    • Shuyong Zhu
    • , Chengjiang Zhao
    • , Yingying Wu
    • , Qiaoqiao Yang
    • , Aiyun Shao
    • , Tiepeng Wang
    • , Jianfu Wu
    • , Yanqing Yin
    • , Yandong Li
    • , Jincan Hou
    • , Xinhua Zhang
    •  & Jiawei Zhou
  2. University of the Chinese Academy of Sciences, Shanghai, China.

    • Chengjiang Zhao
    •  & Yingying Wu
  3. Department of Anatomy, Histology and Embryology, Shanghai Medical School, Fudan University, Shanghai, China.

    • Qiaoqiao Yang
    •  & Guomin Zhou
  4. Co-innovation Center of Neuroregeneration, School of Medicine, Nantong University, Nantong, China.

    • Xinhua Zhang
    •  & Xiaosong Gu
  5. Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing, China.

    • Xiaomin Wang
  6. Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas, University of Salamanca, Salamanca, Spain.

    • Xosé R Bustelo

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Contributions

S.Z. conducted most of the biochemical experiments and the data analysis, and C.Z. conducted most of the in vivo experiments and the data analysis. Y.W. conducted some of the in vivo and in vitro experiments. Q.Y. contributed to the in vitro experiments. A.S. and J.W. contributed to mutant and protein interaction analysis. T.W. contributed to the CPP assay. Y.Y. conducted in situ hybridization; Y.Y., Y.L. and J.H. conducted genotyping; X.Z. contributed to in vitro experiments. X.G., G.Z. and X.W. provided advice; X.R.B. provided Vav2/ and Vav3/ mice and Vav2 and 3 constructs; and J.Z. supervised the project and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jiawei Zhou.

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https://doi.org/10.1038/nn.4060