HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: fj.07-9468comv1 22/3/870    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zador, Z. Articles by Verkman, A. S. Search for Related Content PubMed PubMed Citation Articles by Zador, Z. Articles by Verkman, A. S.

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

²Correspondence: 1246 Health Sciences East Tower, University of California, San Francisco, CA 94143-0521, USA. E-mail: alan.verkman{at}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

This article has been cited by other articles:

				S. Jin, Z. Zador, and A. S. Verkman Random-Walk Model of Diffusion in Three Dimensions in Brain Extracellular Space: Comparison with Microfiberoptic Photobleaching Measurements Biophys. J., August 15, 2008; 95(4): 1785 - 1794. [Abstract] [Full Text] [PDF]

				X. Yao, S. Hrabetova, C. Nicholson, and G. T. Manley Aquaporin-4-Deficient Mice Have Increased Extracellular Space without Tortuosity Change J. Neurosci., May 21, 2008; 28(21): 5460 - 5464. [Abstract] [Full Text] [PDF]