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Astrocytic water channel aquaporin-4 modulates brain plasticity in both mice and humans: a potential gliogenetic mechanism underlying language-associated learning

A Correction to this article was published on 26 July 2021

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Abstract

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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References

  1. 1

    Szu JI, Binder DK . The role of astrocytic aquaporin-4 in synaptic plasticity and learning and Memory. Front Integr Neurosci 2016; 10: 8.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  2. 2

    Simard M, Nedergaard M . The neurobiology of glia in the context of water and ion homeostasis. Neuroscience 2004; 129: 877–896.

    CAS  PubMed  Article  Google Scholar 

  3. 3

    Draganski B, Gaser C, Busch V, Schuierer G, Bogdahn U, May A . Neuroplasticity: changes in grey matter induced by training. Nature 2004; 427: 311–312.

    CAS  PubMed  Article  Google Scholar 

  4. 4

    Kuhn S, Gleich T, Lorenz RC, Lindenberger U, Gallinat J . Playing Super Mario induces structural brain plasticity: gray matter changes resulting from training with a commercial video game. Mol Psychiatry 2014; 19: 265–271.

    CAS  PubMed  Article  Google Scholar 

  5. 5

    Maguire EA, Gadian DG, Johnsrude IS, Good CD, Ashburner J, Frackowiak RS et al. Navigation-related structural change in the hippocampi of taxi drivers. Proc Natl Acad Sci USA 2000; 97: 4398–4403.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6

    Maguire EA, Woollett K, Spiers HJ . London taxi drivers and bus drivers: a structural MRI and neuropsychological analysis. Hippocampus 2006; 16: 1091–1101.

    PubMed  Article  Google Scholar 

  7. 7

    Kempermann G, Kuhn HG, Gage FH . More hippocampal neurons in adult mice living in an enriched environment. Nature 1997; 386: 493–495.

    CAS  PubMed  Article  Google Scholar 

  8. 8

    Susser ER, Wallace RB . The effects of environmental complexity on the hippocampal formation of the adult rat. Acta Neurobiol Exp (Wars) 1982; 42: 203–207.

    CAS  Google Scholar 

  9. 9

    Lee DW, Miyasato LE, Clayton NS . Neurobiological bases of spatial learning in the natural environment: neurogenesis and growth in the avian and mammalian hippocampus. Neuroreport 1998; 9: R15–R27.

    CAS  PubMed  Article  Google Scholar 

  10. 10

    Smulders TV, Sasson AD, DeVoogd TJ . Seasonal variation in hippocampal volume in a food-storing bird, the black-capped chickadee. J Neurobiol 1995; 27: 15–25.

    CAS  PubMed  Article  Google Scholar 

  11. 11

    Fields RD . A new mechanism of nervous system plasticity: activity-dependent myelination. Nat Rev Neurosci 2015; 16: 756–767.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12

    Diamond MC, Scheibel AB, Murphy GM Jr, Harvey T . On the brain of a scientist: Albert Einstein. Exp Neurol 1985; 88: 198–204.

    CAS  PubMed  Article  Google Scholar 

  13. 13

    Falk D, Lepore FE, Noe A . The cerebral cortex of Albert Einstein: a description and preliminary analysis of unpublished photographs. Brain 2013; 136: 1304–1327.

    PubMed  Article  Google Scholar 

  14. 14

    Tait MJ, Saadoun S, Bell BA, Papadopoulos MC . Water movements in the brain: role of aquaporins. Trends Neurosci 2008; 31: 37–43.

    CAS  PubMed  Article  Google Scholar 

  15. 15

    Wang YF, Parpura V . Central role of maladapted astrocytic plasticity in ischemic brain edema formation. Front Cell Neurosci 2016; 10: 129.

    PubMed  PubMed Central  Google Scholar 

  16. 16

    Nielsen S, Nagelhus EA, Amiry-Moghaddam M, Bourque C, Agre P, Ottersen OP . Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci 1997; 17: 171–180.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17

    Williams NM, Rees MI, Holmans P, Norton N, Cardno AG, Jones LA et al. A two-stage genome scan for schizophrenia susceptibility genes in 196 affected sibling pairs. Hum Mol Genet 1999; 8: 1729–1739.

    CAS  PubMed  Article  Google Scholar 

  18. 18

    Mathews CA, Reus VI . Genetic linkage in bipolar disorder. CNS Spectr 2003; 8: 891–904.

    PubMed  Article  Google Scholar 

  19. 19

    Merette C, Bissonnette L, Rouillard E, Roy M, Maziade M . Positive linkage results for bipolar disorder on 18q in large kindreds from eastern Quebec (Abstract). Am J Med Genet 1997; 74: 674.

    Google Scholar 

  20. 20

    Romanos M, Freitag C, Jacob C, Craig DW, Dempfle A, Nguyen TT et al. Genome-wide linkage analysis of ADHD using high-density SNP arrays: novel loci at 5q13.1 and 14q12. Mol Psychiatry 2008; 13: 522–530.

    CAS  PubMed  Article  Google Scholar 

  21. 21

    Kaminsky EB, Kaul V, Paschall J, Church DM, Bunke B, Kunig D et al. An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities. Genet Med 2011; 13: 777–784.

    PubMed  PubMed Central  Article  Google Scholar 

  22. 22

    Isaksen J, Bryn V, Diseth TH, Heiberg A, Schjolberg S, Skjeldal OH . Children with autism spectrum disorders - the importance of medical investigations. Eur J Paediatr Neurol 2013; 17: 68–76.

    PubMed  Article  Google Scholar 

  23. 23

    Arguello PA, Gogos JA . Genetic and cognitive windows into circuit mechanisms of psychiatric disease. Trends Neurosci 2012; 35: 3–13.

    CAS  PubMed  Article  Google Scholar 

  24. 24

    Hackam DG, Redelmeier DA . Translation of research evidence from animals to humans. JAMA 2006; 296: 1731–1732.

    CAS  PubMed  Google Scholar 

  25. 25

    Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 2016; 536: 285–291.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26

    Ventura A, Meissner A, Dillon CP, McManus M, Sharp PA, Van Parijs L et al. Cre-lox-regulated conditional RNA interference from transgenes. Proc Natl Acad Sci USA 2004; 101: 10380–10385.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27

    Rosenzweig MR, Krech D, Bennett EL, Diamond MC . Effects of environmental complexity and training on brain chemistry and anatomy: a replication and extension. J Comp Physiol Psychol 1962; 55: 429–437.

    CAS  PubMed  Article  Google Scholar 

  28. 28

    Cavalieri B . Geometria Degli Indivisibili. Unione Tipografico: Torino, Italy, 1966.

    Google Scholar 

  29. 29

    MacVicar BA, Hochman D . Imaging of synaptically evoked intrinsic optical signals in hippocampal slices. J Neurosci 1991; 11: 1458–1469.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30

    Woo DH, Han KS, Shim JW, Yoon BE, Kim E, Bae JY et al. TREK-1 and Best1 channels mediate fast and slow glutamate release in astrocytes upon GPCR activation. Cell 2012; 151: 25–40.

    CAS  PubMed  Article  Google Scholar 

  31. 31

    Choe AY, Hwang ST, Kim JH, Park KB, Chey J, Hong SH . Validity of the K-WAIS-IV Short Forms. Kor J Clin Psychol 2014; 33: 413–428.

    Article  Google Scholar 

  32. 32

    Huang CC, Liu M-E, Kao H-W, Chou K-H, Yang AC, Wang Y-H et al. Effect of Alzheimer's disease risk variant rs3824968 at SORL1 on regional gray matter volume and age-related interaction in adult lifespan. Sci Rep 2016; 6: 23362.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33

    Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H et al. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 2004; 23 (Suppl 1): S208–S219.

    PubMed  Article  Google Scholar 

  34. 34

    FMRIB Software Library v5 0. Available at https://fsl.fmrib.ox.ac.uk/fsl/fslwiki/ (Accessed 4 January 2017).

  35. 35

    Smith SM . Fast robust automated brain extraction. Hum Brain Mapp 2002; 17: 143–155.

    PubMed  PubMed Central  Article  Google Scholar 

  36. 36

    West BT, Welch KB, Galecki AT . Linear Mixed Models: A Practical Guide Using Statistical Software. Chapman & Hall/CRC: Boca Raton, FL, USA, 2007.

    Google Scholar 

  37. 37

    AFNI program. 3dClustSim. Available at https://afni.nimh.nih.gov/pub/dist/doc/program_help/3dClustSim.html. Accessed 4 January 2017.

  38. 38

    Bennett CM, Wolford GL, Miller MB . The principled control of false positives in neuroimaging. Soc Cogn Affect Neurosci 2009; 4: 417–422.

    PubMed  PubMed Central  Article  Google Scholar 

  39. 39

    Nichols TE . Multiple testing corrections, nonparametric methods, and random field theory. Neuroimage 2012; 62: 811–815.

    PubMed  Article  Google Scholar 

  40. 40

    Benton AL, Hamsher KD, Sivan AB . Multilingual Aphasia Examination: Manual of Instructions 3rd (edn). AJA Associates: Iowa City, IA, USA, 1994.

  41. 41

    Martensson J, Eriksson J, Bodammer NC, Lindgren M, Johansson M, Nyberg L et al. Growth of language-related brain areas after foreign language learning. Neuroimage 2012; 63: 240–244.

    PubMed  Article  Google Scholar 

  42. 42

    Kim JK, Kang Y . Brief report normative study of the Korean-California Verbal Learning Test (K-CVLT). Clin Neuropsychol 1999; 13: 365–369.

    CAS  PubMed  Article  Google Scholar 

  43. 43

    Delis DC, Kramer JH, Kaplan E, Ober BA . CVLT, California Verbal Learning Test: Adult Version: Manual. Psychological Corporation: San Antonio, TX, 1987.

    Google Scholar 

  44. 44

    Delis DC, Freeland J, Kramer JH, Kaplan E . Integrating clinical assessment with cognitive neuroscience: construct validation of the California Verbal Learning Test. J Consult Clin Psychol 1988; 56: 123–130.

    CAS  PubMed  Article  Google Scholar 

  45. 45

    Skucas VA, Mathews IB, Yang J, Cheng Q, Treister A, Duffy AM et al. Impairment of select forms of spatial memory and neurotrophin-dependent synaptic plasticity by deletion of glial aquaporin-4. J Neurosci 2011; 31: 6392–6397.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46

    Penfield W, Roberts L . Speech and Brain-Mechanisms. Princeton University Press: NJ, USA, 1959.

    Book  Google Scholar 

  47. 47

    Posner MI, Raichle ME . Images of Mind. Scientific American Library: NY, USA, 1994.

    Google Scholar 

  48. 48

    Benjamini Y, Hochberg Y . Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc 1995; 57: 289–300.

    Google Scholar 

  49. 49

    Cohen LB, Keynes RD . Changes in light scattering associated with the action potential in crab nerves. J Physiol 1971; 212: 259–275.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50

    Nedergaard M, Ransom B, Goldman SA . New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci 2003; 26: 523–530.

    CAS  PubMed  Article  Google Scholar 

  51. 51

    Li YK, Wang F, Wang W, Luo Y, Wu PF, Xiao JL et al. Aquaporin-4 deficiency impairs synaptic plasticity and associative fear memory in the lateral amygdala: involvement of downregulation of glutamate transporter-1 expression. Neuropsychopharmacology 2012; 37: 1867–1878.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52

    Fan Y, Liu M, Wu X, Wang F, Ding J, Chen J et al. Aquaporin-4 promotes memory consolidation in Morris water maze. Brain Struct Funct 2013; 218: 39–50.

    CAS  PubMed  Article  Google Scholar 

  53. 53

    Yang J, Li MX, Luo Y, Chen T, Liu J, Fang P et al. Chronic ceftriaxone treatment rescues hippocampal memory deficit in AQP4 knockout mice via activation of GLT-1. Neuropharmacology 2013; 75: 213–222.

    CAS  PubMed  Article  Google Scholar 

  54. 54

    Papadopoulos MC, Verkman AS . Aquaporin water channels in the nervous system. Nat Rev Neurosci 2013; 14: 265–277.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55

    Gorelick DA, Praetorius J, Tsunenari T, Nielsen S, Agre P . Aquaporin-11: a channel protein lacking apparent transport function expressed in brain. BMC Biochem 2006; 7: 14.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  56. 56

    Nagelhus EA, Ottersen OP . Physiological roles of aquaporin-4 in brain. Physiol Rev 2013; 93: 1543–1562.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57

    Allen Brain Atlas. Available at http://www.brain-map.org/. Accessed 8 February 2017.

  58. 58

    Friedman B, Schachtrup C, Tsai PS, Shih AY, Akassoglou K, Kleinfeld D et al. Acute vascular disruption and aquaporin 4 loss after stroke. Stroke 2009; 40: 2182–2190.

    PubMed  PubMed Central  Article  Google Scholar 

  59. 59

    Li P, Legault J, Litcofsky KA . Neuroplasticity as a function of second language learning: anatomical changes in the human brain. Cortex 2014; 58: 301–324.

    PubMed  Article  Google Scholar 

  60. 60

    Mamiya PC, Richards TL, Coe BP, Eichler EE, Kuhl PK . Brain white matter structure and COMT gene are linked to second-language learning in adults. Proc Natl Acad Sci USA 2016; 113: 7249–7254.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61

    Rapcsak SZ, Beeson PM . The role of left posterior inferior temporal cortex in spelling. Neurology 2004; 62: 2221–2229.

    PubMed  Article  Google Scholar 

  62. 62

    Nakamura K, Honda M, Okada T, Hanakawa T, Toma K, Fukuyama H et al. Participation of the left posterior inferior temporal cortex in writing and mental recall of kanji orthography: a functional MRI study. Brain 2000; 123 (Pt 5): 954–967.

    PubMed  Article  Google Scholar 

  63. 63

    Kim JJ, Diamond DM . The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci 2002; 3: 453–462.

    CAS  PubMed  Article  Google Scholar 

  64. 64

    McEwen BS . Stress and hippocampal plasticity. Annu Rev Neurosci 1999; 22: 105–122.

    CAS  PubMed  Article  Google Scholar 

  65. 65

    Draganski B, Gaser C, Kempermann G, Kuhn HG, Winkler J, Buchel C et al. Temporal and spatial dynamics of brain structure changes during extensive learning. J Neurosci 2006; 26: 6314–6317.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66

    Adlard PA, Cotman CW . Voluntary exercise protects against stress-induced decreases in brain-derived neurotrophic factor protein expression. Neuroscience 2004; 124: 985–992.

    CAS  PubMed  Article  Google Scholar 

  67. 67

    Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci USA 2011; 108: 3017–3022.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68

    Araujo PR, Yoon K, Ko D, Smith AD, Qiao M, Suresh U et al. Before it gets started: regulating translation at the 5' UTR. Comp Funct Genomics 2012; 2012: 475731.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  69. 69

    Huang HD . A Regulatory RNA Motifs and Elements Finder. Available at http://regrna.mbc.nctu.edu.tw/index1.php. Accessed 18 February 2017.

  70. 70

    Lan YL, Fang DY, Zhao J, Ma TH, Li S . A research update on the potential roles of aquaporin 4 in neuroinflammation. Acta Neurol Belg 2016; 116: 127–134.

    PubMed  Article  Google Scholar 

  71. 71

    Xiao M, Hu G . Involvement of aquaporin 4 in astrocyte function and neuropsychiatric disorders. CNS Neurosci Ther 2014; 20: 385–390.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72

    The Broad Institute of MIT and Harvard. GTEx Portal. Available at http://www.gtexportal.org/home/gene/AQP4. Accessed 14 February 2017.

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Acknowledgements

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.

Author contributions

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.

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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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