Abstract
The heterogeneous contents of the CNS interstitial clefts and the configuration of their astrocytic walls may be regionally variable. Astrocytic processes of the glia limitans, in normal midbrain and in astroglial scars, form thin, parallel, concentric sheets comprising the walls of narrow interstitial clefts. There is a critical thickness of about 20 to 30 nm, below which astrocytic cell process or those of the fibroblast-like cells in the meninges, do not invaginate to form transcytotic vesicles. Large hydrophilic solutes cannot, therefore, pass across the thin portion of a cell process. Consequently, (a) the diffusion and convection paths of interstitial fluid and solutes are lengthened, (b) a solute will remain within the interstitial cleft between thin lamellae for a relatively long time and (c) if a ligand does bind to its receptor on the thin process's cell membrane, there can be no receptor-mediated transcytosis at that site. Interstitial clefts, themselves, vary in size, shape and content, including extracellular matrix and basal lamina. A common constituent of basal lamina and extracellular matrix, presumably including that at ependymal, astroglial and endothelial interfaces of the CNS, is heparan sulfate proteoglycans. As in other organs, these proteoglycans may store growth factors, growth inhibitors, cytokines and other modulators which can then be released enzymatically during, e.g., regeneration. Exogenous heparan sulfate proteoglycan might serve as a natural, intermittent-release matrix for delivery of trophic factors.
Similar content being viewed by others
References
Anders, J. J. & Brightman, M. W. (1986) Freezefracture studies of plasma membranes of astrocytes in freezing lesions. Advances in Neurology 44, 765–774.
Brightman, M. W. (1965a) The distribution within the brain of ferritin injected into cerebrospinal fluid compartments. I. Ependymal distribution. Journal of Cell Biology 26, 99–123.
Brightman, M. W. (1965b) The distribution within the brain of ferritin injected into cerebrospinal fluid compartments. II. Parenchymal distribution. American Journal of Anatomy 117, 193–219.
Brightman, M. W. (1968) The intracerebral movement of proteins injected into blood and cerebrospinal fluid of mice. Progress in Brain Research 29, 19–37.
Brightman, M. W. & Kaya, M. (2000) Permeable endothelium and the interstitial space of brain. Cellular & Molecular Neurobiology 20, 111–130.
Bundgaard, M. & Cserr, H. F. (1991) Barrier membranes at the outer surface of the brain of an elasmobranch, Raja erinacea. Cell and Tissue Research 265, 113–120.
Chodobski, A. & Szmydynger-Chodobska, J. (2001) Choroid plexus: Target for polypeptides and site of their synthesis. Microscopy Research and Technique 52, 65–82.
Deguchi, Y., Okutsu, H., Okura, T., Yamada, S., Kimura, R., Yuge, T., Furukawa, A., Morimoto, K., Tachikawa, M., Otsuki, S., Hosoya, K. & Terasaki, T. (2002) Internalization of basic fibroblast growth factor at the mouse blood-brain barrier involves perlecan, a heparan sulfate proteoglycan. Journal of Neurochemistry 83, 381–389.
Dixelius, J., Larsson, H., Sasaki, T., Holmqvist, K., Lu, L., Engsrton, A., Timpl, R., Welsh, M. & Claesson-Welsh, L. (2000) Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis. Blood 95, 3403–3411.
Elkin, M., Ilan, N., Ishai-Michaeli, R., Friedmann, Y., Pao, O., Pecker, I. & Vlodavsky, I. (2001) Heparanase as mediator of angiogenesis: Mode of action. Federation of American Society of Experimental Biology Journal 15, 1661–1663.
Falcone, D. J., Mccaffrey, T. A., Haimovitzfriedman, A., Vergilio, J.-A. & Nicholson, A. C. (1993) Macrophage and foam cell release of matrixbound growth factors. Journal of Biological Chemistry 268, 11951–11958.
Folkman, J., Klagsburn, M., Sasse, J., Wadzinski, M., Ingber, D. & Vlodavsky, I. (1988) A heparin-binding angiogenic protein-basic fibroblast growth factor is stored within basement membrane. American Journal of Pathology 130, 393–400.
Garcia de Yebenes, E., Ho, A., Damani, T., Fillit, H. & Blum, M. (1999) Regulation of the heparan sulfate proteoglycan, perlecan, by injury and interleukin-1 alpha. Journal of Neurochemistry 73, 812–820.
Ghersi-Egea, J.-F., Finnegan, W., Chen, J.-L. & Fenstermacher, J. D. (1996) Rapid distribution of intraventricularly administered sucrose into cerebrospinal fluid cisterns via subarachnoid velae in rat. Neuroscience 75, 1271–1288.
Graeber, M. B. & Kreutzberg, G. W. (1988) Delayed astrocyte reaction following facial nerve axotomy. Journal of Neurocytology 17, 209–220.
Guntinas-Lichius, O., Martinez-Portillo, F., Lebek, J., Angelov, D. N., Stennert, E. & Neiss, W. F. (1997) Nimodipine maintains in vivo the increase in GFAP and enhances the astroglial ensheathment of surviving motoneurons in the rat following permanent target deprivation. Journal of Neurocytology 26, 247–248.
Handler, M., Yurchenko, P. D. & Iozzo, R. V. (1997) Developmental expression of perlecan during murine embryogenesis. Developmental Dynamics 210, 130–145.
Hardingham, T. E. & Fosang, A. J. (1992) Proteoglycans: Many forms and many functions. Federation of the American Society for Experimental Biology Journal 6, 861–870.
Iozzo, R. V. & San antonio, J. D. (2001) Heparan sulfate proteoglycans: Heavy hitters in the angiogenesis arena. Journal of Clinical Investigation 108, 349–355.
Knox, S. Merry, C., Stringer, S., Melrose, J. & Whitelock, J. (2002) Not all perlecans are created equal. Journal of Biological Chemistry 277, 14657–14665.
Krautstrunk, M., Scholtes, F., Martin, D., Schoenen, J., Schmitt, A. B., Plate, D., Nacimiento, W., Noth, J. & Brook, G. A. (2002) Increased expression of the putative axon growthrepulsive extracellular matrix molecule, keratan sulphate proteoglycan, following traumatic injury of the adult rat spinal cord. Acta Neuropathologica 104, 592–600.
Laurie, G. W., Inoue, S., Bing, J. T. & Hassell, J. R. (1988) Visualization of the large heparan sulfate proteoglycan from basement membrane. American Journal of Anatomy 181, 320–326.
Lieberman, D. M., Laske, D. W., Morrison, P. F., Bankiewicz, K. S. & Oldfield, E. H. (1995) Convection-enhanced distribution of large molecules in gray matter during interstitial drug infusion. Journal of Neurosurgery 82, 1021–1029.
Lortat-Jacob, H., Turnbull, J. E. & Grimaud, J.-A. (1995) Molecular organization of the interferon-γ binding domain in heparan sulphate. Biochemical Journal 310, 497–505.
Mercier, F., Kitasako, J. T. & Hatton, G. I. (2003) Fractones and other basal laminae in the hypothalamus. Journal of Comparative Neurology 455, 324–340.
Moon, L. D., Asher, R. A., Rhodes, K. E. & Fawcett, J. W. (2002) Relationship between sprouting axons, proteoglycans and glial cells following unilateral nigrostriatal axotomy in the adult rat. Neuroscience 109, 101–117.
Murdoch, A. D. & Iozzo, R. V. (1993) Perlecan: The multidomain heparan sulphate proteoglycan of basement membrane and extracellular matrix. Virchows Archives A. Pathological Anatomy and Histopathology 423, 237–242.
Nabeshima, S., Reese, T. S., Landis, D. M. D. & Brightman, M. W. (1975) Junctions in the meninges and marginal glia. Journal of Comparative Neurology 164, 127–170.
Nader, H. B., Dietrich, C. P., Buonassi, V. & Colburn, P. (1987) Heparin sequences in the heparan sulfate chains of an endothelial proteoglycan. Proceedings of the National Academy of Sciences USA 84, 3565–3569.
Naito, S., Chang, L., Pettigrew, K., Ishihara, S. & Brightman, M. (1995) Conditions that may determine blood vessel phenotype in tissues grafted to brain. Experimental Neurology 134, 230–243.
Nicholson, C. & Tao, L. (1993) Hindered diffusion of high molecular weight compounds in brain extracellular microenvironment measured with integrative optical imaging. Biophysical Journal 65, 2277–2290.
Phillipe, J. M., Dubois, J. M., Rouzaire-Dubois, B., Cartron, P. F., Vallette, F. & Morel, N. (2002) Functional expression of V-ATPases in the plasma membrane of glial cells. Glia 37, 365–373.
Reese, T. S. & Brightman, M. W. (1965) Electronmicroscopic studies on the olfactory bulb. Anatomical Record 151, 492.
Sasaki, T., Larsson, H., Kreuger, J., Salmivirta, M., Claesson-Welsh, L., Lindahl, U., Hohenester, E. & Timpl, R. (1999) Structural basis and potential role of heparin/heparan sulfate binding to the angiogenesis inhibitor endostatin. European Molecular Biology Organization Journal 22, 6240–6248.
Shaver, S. W., Pang, J. J., Wall, K. M., Sposito, N. M. & Gross, P. (1991) Subregional topography of capillaries in the dorsal vagal complex of rats: I. Morphometric properties. Journal of Comparative Neurology 306, 73–82.
Silva, R. F., Mata, L. M., Gulbenkian, S. & Brites, D. (2001) Endocytosis in rat cultured astrocytes is inhibited by unconjugated bilirubin. Neurochemical Research 26, 793–800.
Spillmann, D., Witt, D. & Lindahl, U. (1998) Defining the interleukin-8 binding domain of heparan sulfate. Journal of Biological Chemistry 273, 15487–15493.
Szentagothai, J. (1970) Glomerular synapses, complex synaptic arrangements and their operational significance. In The Neurosciences Second Study Program (edited by Scmitt, F. O.) pp. 427–443. New York: Rockefeller Press.
Tabernero, A., Velasco, A., Granda, B., Lavado, E. M. & Medina, J. M. (2002) Trasncytosis of albumin in astrocytes activates the sterol regulatory element-binding protein-1, which promotes the synthesis of the neurotrophic factor oleic acid. Journal of Biological Chemistry 277, 4240–4246.
Taipale, J. & Keski-Oja, J. (1997) Growth factors in the extracellular matrix. Federation of American Society of Experimental Biology Journal 11, 51–59.
van Houten, M. & Brawer, J. R. (1978) Regional variations in glia and neuropil within the hypothalamic ventromedial nucleus. Journal of Comparative Neurology 179, 719–738.
Vlodavsky, I., Folkman, J., Sullivan, R., Fridman, R., Ishai-michaeli, R., Sasse, J. & Klagsbrun, M. (1987) Endothelial cell-derived basic fibroblast growth factor: Synthesis and deposition into The brain's interstitial clefts 603 subendothelial extracellular matirx. Proceedings of the National Academy of Sciences, USA 84, 2292–2296.
Weindl, A. & Sofroniew, M. V. (1981) Relation of neuropeptides to mammalian circumventricular organs. Advances in Biochemistry and Psychopharmacology 28, 303–320.
Whitelock, J. M., Murdoch, A. D., Iozzo, R. V. & Underwood, P. A. (1996) The degradation of human endothelial cell-derived perlecan and release of bound basic fibroblast growth factor by stromelysin, collagenase, plasmin and heparanases. Journal of Biological Chemistry 271, 10079–10086.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Brightman, M.W. The brain's interstitial clefts and their glial walls. J Neurocytol 31, 595–603 (2002). https://doi.org/10.1023/A:1025783326667
Issue Date:
DOI: https://doi.org/10.1023/A:1025783326667