Environmental enrichment enhances synaptic plasticity by internalization of striatal dopamine transporters

Myung Sun Kim, Ji Hea Yu, Chul Hoon Kim, Jae Yong Choi, Jung Hwa Seo, Min Young Lee, Chi Hoon Yi, Tae Hyun Choi, Young Hoon Ryu, Jong Eun Lee, Bae Hwan Lee, Hyongbum Kim, Sung Rae Cho

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Abstract

Environmental enrichment (EE) with a complex combination of physical, cognitive and social stimulations enhances synaptic plasticity and behavioral function. However, the mechanism remains to be elucidated in detail. We aimed to investigate dopamine-related synaptic plasticity underlying functional improvement after EE. For this, six-week-old CD-1 mice were randomly allocated to EE or standard conditions for two months. EE significantly enhanced behavioral functions such as rotarod and ladder walking tests. In a [ 18 F]FPCIT positron emission tomography scan, binding values of striatal DAT were significantly decreased approximately 18% in the EE mice relative to the control mice. DAT inhibitor administrated to establish the relationship of the DAT down-regulation to the treatment effects also improved rotarod performances, suggesting that DAT inhibition recapitulated EE-mediated treatment benefits. Next, EE-induced internalization of DAT was confirmed using a surface biotinylation assay. In situ proximity ligation assay and immunoprecipitation demonstrated that EE significantly increased the phosphorylation of striatal DAT as well as the levels of DAT bound with protein kinase C (PKC). In conclusion, we suggest that EE enables phosphorylation of striatal DAT via a PKC-mediated pathway and causes DAT internalization. This is the first report to suggest an EE-mediated mechanism of synaptic plasticity by internalization of striatal DAT.

Original languageEnglish
Pages (from-to)2122-2133
Number of pages12
JournalJournal of Cerebral Blood Flow and Metabolism
Volume36
Issue number12
DOIs
Publication statusPublished - 2016 Dec 1

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All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

Cite this

Kim, M. S., Yu, J. H., Kim, C. H., Choi, J. Y., Seo, J. H., Lee, M. Y., Yi, C. H., Choi, T. H., Ryu, Y. H., Lee, J. E., Lee, B. H., Kim, H., & Cho, S. R. (2016). Environmental enrichment enhances synaptic plasticity by internalization of striatal dopamine transporters. Journal of Cerebral Blood Flow and Metabolism, 36(12), 2122-2133. https://doi.org/10.1177/0271678X15613525