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Loss or Mislocalization of Aquaporin-4 Affects Diffusion Properties and Intermediary Metabolism in Gray Matter of Mice

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Abstract

The first aim of this study was to determine how complete or perivascular loss of aquaporin-4 (AQP4) water channels affects membrane permeability for water in the mouse brain grey matter in the steady state. Time-dependent diffusion magnetic resonance imaging was performed on global Aqp4 knock out (KO) and α-syntrophin (α-syn) KO mice, in the latter perivascular AQP4 are mislocalized, but still functioning. Control animals were corresponding wild type (WT) mice. By combining in vivo diffusion measurements with the effective medium theory and previously measured extra-cellular volume fractions, the effects of membrane permeability and extracellular volume fraction were uncoupled for Aqp4 and α-syn KO. The second aim was to assess the effect of α-syn KO on cortical intermediary metabolism combining in vivo [1-13C]glucose and [1,2-13C]acetate injection with ex vivo 13C MR spectroscopy. Aqp4 KO increased the effective diffusion coefficient at long diffusion times by 5%, and a 14% decrease in membrane water permeability was estimated for Aqp4 KO compared with WT mice. α-syn KO did not affect the measured diffusion parameters. In the metabolic analyses, significantly lower amounts of [4-13C]glutamate and [4-13C]glutamine, and percent enrichment in [4-13C]glutamate were detected in the α-syn KO mice. [1,2-13C]acetate metabolism was unaffected in α-syn KO, but the contribution of astrocyte derived metabolites to GABA synthesis was significantly increased. Taken together, α-syn KO mice appeared to have decreased neuronal glucose metabolism, partly compensated for by utilization of astrocyte derived metabolites.

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Acknowledgements

The funding was provided by The Liaison Committee between the Central Norway Regional Health Authority and NTNU, Norwegian National Advisory Unit for functional MRI, St. Olavs hospital, Trondheim University hospital, Norway, Norges Forskningsråd (NO) (Grant No. 226696) and Research Council of Norway (Grant No. 240476).

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Authors and Affiliations

  1. Department of Circulation and Medical Imaging, Faculty of Medicine, NTNU, Trondheim, Norway

    T. Pavlin, C. Brekken & O. Haraldseth

  2. Department of Biomedicine, Molecular Imaging Center, University of Bergen, Bergen, Norway

    T. Pavlin

  3. Department of Molecular Medicine, Faculty of Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway

    E. A. Nagelhus, A. Thoren & O. P. Ottersen

  4. Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), 7489, Trondheim, Norway

    E. M. Eyjolfsson, U. Sonnewald & A. K. Håberg

  5. Department of Drug Design and Pharmacology, Faculty of Health and Medicine, University of Copenhagen, 2100, Copenhagen, Denmark

    U. Sonnewald

  6. Department of Radiology and Nuclear Medicine, St. Olavs, Trondheim University Hospital, Trondheim, Norway

    A. K. Håberg

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Pavlin, T., Nagelhus, E.A., Brekken, C. et al. Loss or Mislocalization of Aquaporin-4 Affects Diffusion Properties and Intermediary Metabolism in Gray Matter of Mice. Neurochem Res 42, 77–91 (2017). https://doi.org/10.1007/s11064-016-2139-y

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