title: Environmental enrichment enhances synaptic plasticity by internalization of striatal dopamine transporters.
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.
authors.affiliation: Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, Korea.|Yonsei Stem Cell Center, Avison Biomedical Research Center, Seoul, Korea.
authors.forename: Myung-Sun
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, Korea.|Department of Medical Science, The Graduate School, Yonsei University, Seoul, Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.
authors.forename: Ji Hea
authors.initials: JH
authors.lastname: Yu
authors.affiliation: Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.|Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea.|Brain Research Institute, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Chul Hoon
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea.|Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jae Yong
authors.initials: JY
authors.lastname: Choi
authors.affiliation: Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.
authors.forename: Jung Hwa
authors.initials: JH
authors.lastname: Seo
authors.affiliation: Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, Korea.|Yonsei Stem Cell Center, Avison Biomedical Research Center, Seoul, Korea.
authors.forename: Min-Young
authors.initials: MY
authors.lastname: Lee
authors.affiliation: Department of Molecular Imaging, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Chi Hoon
authors.initials: CH
authors.lastname: Yi
authors.affiliation: Department of Molecular Imaging, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Tae Hyun
authors.initials: TH
authors.lastname: Choi
authors.affiliation: Department of Nuclear Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Ryu
authors.affiliation: Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.|Brain Research Institute, Yonsei University College of Medicine, Seoul, Korea.|Department of Anatomy, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jong Eun
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.|Brain Research Institute, Yonsei University College of Medicine, Seoul, Korea.|Department of Physiology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Bae Hwan
authors.initials: BH
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hyongbum
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, Korea srcho918@yuhs.ac.|Yonsei Stem Cell Center, Avison Biomedical Research Center, Seoul, Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.|Rehabilitation Institute of Neuromuscular Disease, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Sung-Rae
authors.initials: SR
authors.lastname: Cho
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000737:chemistry; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D004705:Endocytosis; D004777:Environment; D051379:Mice; D009473:Neuronal Plasticity; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D011493:Protein Kinase C
keywords: Dopamine transporter; environmental enrichment; internalization; phosphorylation