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Front Neurol. 2018 Jul 16;9:465. doi: 10.3389/fneur.2018.00465. eCollection 2018.

Environmental Enrichment Upregulates Striatal Synaptic Vesicle-Associated Proteins and Improves Motor Function.

Song SY1,2, Chae M1,3, Yu JH1, Lee MY1, Pyo S1,4, Shin YK1,4, Baek A1,5, Park JW6, Park ES1, Choi JY1,7, Cho SR1,2,3,4.

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Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, South Korea.
Graduate Program of NanoScience and Technology, Yonsei University, Seoul, South Korea.
Rehabilitation Institute of Neuromuscular Disease, Yonsei University College of Medicine, Seoul, South Korea.
Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, South Korea.
Department of Rehabilitation Medicine, Yonsei University Wonju College of Medicine, Wonju, South Korea.
Department of Medicine, Yonsei University College of Medicine, Seoul, South Korea.
Department of Rehabilitation Medicine, Eulji University School of Medicine, Daejeon, South Korea.


Environmental enrichment (EE) is a therapeutic paradigm that consists of complex combinations of physical, cognitive, and social stimuli. The mechanisms underlying EE-mediated synaptic plasticity have yet to be fully elucidated. In this study, we investigated the effects of EE on synaptic vesicle-associated proteins and whether the expression of these proteins is related to behavioral outcomes. A total of 44 CD-1® (ICR) mice aged 6 weeks were randomly assigned to either standard cages or EE (N = 22 each). Rotarod and ladder walking tests were then performed to evaluate motor function. To identify the molecular mechanisms underlying the effects of EE, we assessed differentially expressed proteins (DEPs) in the striatum by proteomic analysis. Quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and immunohistochemistry were conducted to validate the expressions of these proteins. In the behavioral assessment, EE significantly enhanced performance on the rotarod and ladder walking tests. A total of 116 DEPs (54 upregulated and 62 downregulated proteins) were identified in mice exposed to EE. Gene ontology (GO) analysis demonstrated that the upregulated proteins in EE mice were primarily related to biological processes of synaptic vesicle transport and exocytosis. The GO terms for these biological processes commonly included Synaptic vesicle glycoprotein 2B (SV2B), Rabphilin-3A, and Piccolo. The qRT-PCR and western blot analyses revealed that EE increased the expression of SV2B, Rabphilin-3A and Piccolo in the striatum compared to the control group. Immunohistochemistry showed that the density of Piccolo in the vicinity of the subventricular zone was significantly increased in the EE mice compared with control mice. In conclusion, EE upregulates proteins associated with synaptic vesicle transport and exocytosis such as SV2B, Rabphilin-3A and Piccolo in the striatum. These upregulated proteins may be responsible for locomotor performance improvement, as shown in rotarod and ladder walking tests. Elucidation of these changes in synaptic protein expression provides new insights into the mechanism and potential role of EE.


enriched environment; exocytosis; synaptic plasticity; synaptic vesicle; transport

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