Gliotoxin-induced swelling of astrocytes hinders diffusion in brain extracellular space via formation of dead-space microdomains

Authors

  • Ang Doma Sherpa,

    1. Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York
    2. Neural and Behavioral Science Graduate Program, State University of New York Downstate Medical Center, Brooklyn, New York
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  • Paula van de Nes,

    1. Molecular and Cellular Biology Graduate Program, State University of New York Downstate Medical Center, Brooklyn, New York
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  • Fanrong Xiao,

    1. Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York
    2. The Robert F. Furchgott Center for Neural and Behavioral Science, State University of New York Downstate Medical Center, Brooklyn, New York
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  • Jeremy Weedon,

    1. Scientific Computing Center, State University of New York Downstate Medical Center, Brooklyn, New York
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  • Sabina Hrabetova

    Corresponding author
    1. Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York
    2. The Robert F. Furchgott Center for Neural and Behavioral Science, State University of New York Downstate Medical Center, Brooklyn, New York
    • Address correspondence to Sabina Hrabetova, Department of Cell Biology, SUNY Downstate Medical Center, 450 Clarkson Avenue, MSC 5, Brooklyn, NY 11203, USA. E-mail: sabina.hrabetova@downstate.edu

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Abstract

One of the hallmarks of numerous life-threatening and debilitating brain diseases is cellular swelling that negatively impacts extracellular space (ECS) structure. The ECS structure is determined by two macroscopic parameters, namely tortuosity (λ) and volume fraction (α). Tortuosity represents hindrance imposed on the diffusing molecules by the tissue in comparison with an obstacle-free medium. Volume fraction is the proportion of tissue volume occupied by the ECS. From a clinical perspective, it is essential to recognize which factors determine the ECS parameters and how these factors change in brain diseases. Previous studies demonstrated that dead-space (DS) microdomains increased λ during ischemia and hypotonic stress, as these pocket-like structures transiently trapped diffusing molecules. We hypothesize that astrocytes play a key role in the formation of DS microdomains because their thin processes have concave shapes that may elongate as astrocytes swell in these pathologies. Here we selectively swelled astrocytes in the somatosensory neocortex of rat brain slices with a gliotoxin DL-α-Aminoadipic Acid (DL-AA), and we quantified the ECS parameters using Integrative Optical Imaging (IOI) and Real-Time Iontophoretic (RTI) diffusion methods. We found that α decreased and λ increased during DL-AA application. During recovery, α was restored whereas λ remained elevated. Increase in λ during astrocytic swelling and recovery is consistent with the formation of DS microdomains. Our data attribute to the astrocytes an important role in determining the ECS parameters, and indicate that extracellular diffusion can be improved not only by reducing the swelling but also by disrupting the DS microdomains. GLIA 2014;62:1053–1065

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