Microfiberoptic fluorescence photobleaching reveals size-dependent macromolecule diffusion in extracellular space deep in brain Zsolt Zador * ,† , Mazin Magzoub * ,1 , Songwan Jin * ,1 , Geoffrey T. Manley † , Marios C. Papadopoulos * ,‡ and A. S. Verkman * ,2 * Departments of Medicine and Physiology and † Neurological Surgery, University of California, San Francisco, California, USA; and ‡ Academic Neurosurgery Unit, St. George’s University of London, Tooting, London, UK 2 Correspondence: 1246 Health Sciences East Tower, University of California, San Francisco, CA 94143-0521, USA. E-mail: alan.verkman@ucsf.edu Diffusion in brain extracellular space (ECS) is important for nonsynaptic intercellular communication, extracellular ionic buffering, and delivery of drugs and metabolites. We measured macromolecular diffusion in normally light-inaccessible regions of mouse brain by microfiberoptic epifluorescence photobleaching, in which a fiberoptic with a micron-size tip is introduced deep in brain tissue. In brain cortex, the diffusion of a noninteracting molecule fluorescein isothiocyanate (FITC)-dextran, 70 kDa was slowed 4.5 ± 0.5-fold compared with its diffusion in water ( D o / D ), and was depth-independent down to 800 µm from the brain surface. Diffusion was significantly accelerated ( D o / D of 2.9±0.3) in mice lacking the glial water channel aquaporin-4. FITC-dextran diffusion varied greatly in different regions of brain, with D o / D of 3.5 ± 0.3 in hippocampus and 7.4 ± 0.3 in thalamus. Remarkably, D o / D in deep brain was strongly dependent on solute size, whereas diffusion in cortex changed little with solute size. Mathematical modeling of ECS diffusion required nonuniform ECS dimensions in deep brain, which we call "heterometricity," to account for the size-dependent diffusion. Our results provide the first data on molecular diffusion in ECS deep in brain in vivo and demonstrate previously unrecognized hindrance and heterometricity for diffusion of large macromolecules in deep brain.—Zador, Z., Magzoub, M., Jin, S., Manley, G. T., Papadopoulos, M. C., Verkman, A. S. Microfiberoptic fluorescence photobleaching reveals size-dependent macromolecule diffusion in extracellular space deep in brain. Key Words: central nervous system • aquaporin 4
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Microfiberoptic fluorescence photobleaching reveals size-dependent macromolecule diffusion in extracellular space deep in brain
Zador, Zsolt; Magzoub, Mazin; Jin, Songwan; Manley, Geoffrey T.; Papadopoulos, Marios C.; Verkman, A. S.
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, Volume 22 (3): 870
Fed of American Socs for Experimental Biology – Mar 1, 2008
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