The role of astrocytes in brain plasticity has not been extensively studied compared with that of neurons. Here we adopted integrative translational and reverse-translational approaches to explore the role of an astrocyte-specific major water channel in the brain, aquaporin-4 (AQP4), in brain plasticity and learning. We initially identified the most prevalent genetic variant of AQP4 (single nucleotide polymorphism of rs162008 with C or T variation, which has a minor allele frequency of 0.21) from a human database (n=60 706) and examined its functionality in modulating the expression level of AQP4 in an in vitro luciferase reporter assay. In the following experiments, AQP4 knock-down in mice not only impaired hippocampal volumetric plasticity after exposure to enriched environment but also caused loss of long-term potentiation after theta-burst stimulation. In humans, there was a cross-sectional association of rs162008 with gray matter (GM) volume variation in cortices, including the vicinity of the Perisylvian heteromodal language area (Sample 1, n=650). GM volume variation in these brain regions was positively associated with the semantic verbal fluency. In a prospective follow-up study (Sample 2, n=45), the effects of an intensive 5-week foreign language (English) learning experience on regional GM volume increase were modulated by this AQP4 variant, which was also associated with verbal learning capacity change. We then delineated in mice mechanisms that included AQP4-dependent transient astrocytic volume changes and astrocytic structural elaboration. We believe our study provides the first integrative evidence for a gliogenetic basis that involves AQP4, underlying language-associated brain plasticity.
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This study was supported by grants from the Creative Research Initiative Program, National Research Foundation of Korea (2015R1A3A2066619), KIST Institutional Grant (2E26662), KU-KIST Graduate School of Science and Technology program (R1435281; to CJL), Fire Fighting Safety & 119 Rescue Technology Research and Development Program funded by the Ministry of Public Safety and Security (MPSS-Fire Fighting Safety-2016-86 (to JEK) and the Brain Research Program through the National Research Foundation of Korea, funded by the Ministry of Science, ICT and Future Planning (2015M3C7A1028373 and 2015M3C7A1028376; to IKL and JEK). We thank Siyoung Yu, MS, Sungeun Kim, MS, Heejung Hyun, MS, Yera Choi, MS, Eunji Ha, BS, Haejin Hong, BS, Suji L Lee, PharmD and Shinwon Park, MA for their technical assistance.
JW, JEK, IKL and CJL designed and supervised the study. JW, JEK, IKL and CJL wrote the manuscript with input from all authors. JW and JL performed electrophysiological experiments in mice. JEK, JJI, JM, IK and IKL coordinated the conduct of human studies. JEK, HSJ, SML, SL, JM and EYS analyzed the brain image data. JEK, HSJ, JM and IKL conducted and confirmed statistical analyses in human experiments. SP, HA, HC and BEY performed the immunohistochemistry. SYJ carried out luciferase assay. As an experienced neuroradiologist, SML screened all T1-weighted, T2-weighted and fluid-attenuated inversion recovery (FLAIR) images for any gross brain abnormalities. Non-brain tissues remaining after GM segmentation were removed by EYS. YEH developed the AQP4 shRNA. BK, JM and EHL contributed to the genotyping data analyses and interpretation. LF analyzed the single astrocyte volume imaging data. JEK, JJI, HSJ, SY, SML, JM, EYS, IK, SRD and IKL participated in the interpretation of results from human data analyses. All authors provided critical intellectual contribution to the writing and revision of the manuscript.
The authors declare no conflict of interest.
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Woo, J., Kim, J., Im, J. et al. Astrocytic water channel aquaporin-4 modulates brain plasticity in both mice and humans: a potential gliogenetic mechanism underlying language-associated learning. Mol Psychiatry 23, 1021–1030 (2018). https://doi.org/10.1038/mp.2017.113
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