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J Cereb Blood Flow Metab. 2016 Dec;36(12):2122-2133. Epub 2015 Nov 2.

Environmental enrichment enhances synaptic plasticity by internalization of striatal dopamine transporters.

Kim MS1,2, Yu JH1,3,4, Kim CH4,5,6, Choi JY5,7, Seo JH1,4, Lee MY1,2, Yi CH8, Choi TH8, Ryu YH7, Lee JE4,6,9, Lee BH4,6,10, Kim H5, Cho SR11,2,4,12.

Author information

1
Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, Korea.
2
Yonsei Stem Cell Center, Avison Biomedical Research Center, Seoul, Korea.
3
Department of Medical Science, The Graduate School, Yonsei University, Seoul, Korea.
4
Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.
5
Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea.
6
Brain Research Institute, Yonsei University College of Medicine, Seoul, Korea.
7
Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul, Korea.
8
Department of Molecular Imaging, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
9
Department of Anatomy, Yonsei University College of Medicine, Seoul, Korea.
10
Department of Physiology, Yonsei University College of Medicine, Seoul, Korea.
11
Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, Korea srcho918@yuhs.ac.
12
Rehabilitation Institute of Neuromuscular Disease, Yonsei University College of Medicine, Seoul, Korea.

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 [18F]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.

KEYWORDS:

Dopamine transporter; environmental enrichment; internalization; phosphorylation

PMID:
26661218
PMCID:
PMC5363660
DOI:
10.1177/0271678X15613525
[Indexed for MEDLINE]
Free PMC Article

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