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, Jongeun Lee, Bae Hwan Lee, Hyongbum Kim, Sung-Rae Cho

Research output: Contribution to journalArticle

13 Citations (Scopus)

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

Fingerprint

Corpus Striatum
Dopamine Plasma Membrane Transport Proteins
Neuronal Plasticity
Protein Kinase C
Phosphorylation
Biotinylation
Immunoprecipitation
Positron-Emission Tomography
Walking
Ligation
Dopamine
Down-Regulation

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

Cite this

Kim, Myung Sun ; Yu, Ji Hea ; Kim, Chul Hoon ; Choi, Jae Yong ; Seo, Jung Hwa ; Lee, Min Young ; Yi, Chi Hoon ; Choi, Tae Hyun ; Ryu, Young Hoon ; Lee, Jongeun ; Lee, Bae Hwan ; Kim, Hyongbum ; Cho, Sung-Rae. / Environmental enrichment enhances synaptic plasticity by internalization of striatal dopamine transporters. In: Journal of Cerebral Blood Flow and Metabolism. 2016 ; Vol. 36, No. 12. pp. 2122-2133.
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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.",
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Kim, MS, Yu, JH, Kim, CH, Choi, JY, Seo, JH, Lee, MY, Yi, CH, Choi, TH, Ryu, YH, Lee, J, Lee, BH, Kim, H & Cho, S-R 2016, 'Environmental enrichment enhances synaptic plasticity by internalization of striatal dopamine transporters', Journal of Cerebral Blood Flow and Metabolism, vol. 36, no. 12, pp. 2122-2133. https://doi.org/10.1177/0271678X15613525

Environmental enrichment enhances synaptic plasticity by internalization of striatal dopamine transporters. / Kim, Myung Sun; Yu, Ji Hea; Kim, Chul Hoon; Choi, Jae Yong; Seo, Jung Hwa; Lee, Min Young; Yi, Chi Hoon; Choi, Tae Hyun; Ryu, Young Hoon; Lee, Jongeun; Lee, Bae Hwan; Kim, Hyongbum; Cho, Sung-Rae.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 36, No. 12, 01.12.2016, p. 2122-2133.

Research output: Contribution to journalArticle

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AU - Kim, Myung Sun

AU - Yu, Ji Hea

AU - Kim, Chul Hoon

AU - Choi, Jae Yong

AU - Seo, Jung Hwa

AU - Lee, Min Young

AU - Yi, Chi Hoon

AU - Choi, Tae Hyun

AU - Ryu, Young Hoon

AU - Lee, Jongeun

AU - Lee, Bae Hwan

AU - Kim, Hyongbum

AU - Cho, Sung-Rae

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N2 - 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.

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