HOW DO MATERIALS EXCHANGE BETWEEN BLOOD AND NERVE CELLS IN THE BRAIN? STEPHEN W. KVFFLER* AND JOHN G. NICHOLLSÌ Ralph Gerard's willingness to assist young people in their careers was already well known in the closing days ofWorld War II. At that time the reorganization of the Kanematsu Institute in Sydney, Australia, yielded one young neurophysiologist (S. W. K.) who was looking for a newjob. It was natural to turn to R. G., who promptly arranged for a fellowship at the Department ofPhysiology ofthe University ofChicago, thus launching another new scientific career in the U.S.A. R. G.'s laboratory in 1945 was also in the throes ofreorganization, full ofeager young people who faced the future with cautious optimism. It was not obvious to us then that the coming twenty years would see an unprecedented development in the sciences, giving us wonderful chances to lead full and interesting lives. R. G., however, was one ofthose who had a clearer view ofthings to come and he helped shape them. In this discussion we wish to single out two questions which relate to the physiology ofthe central nervous system; they appear rather simple, yet surprisingly have no satisfactory answers. First, what is the function of glial cells? Second, by what pathways do substances exchange between capillaries and nerve cells? We shall see that an answer has to be found to the latter question before one can proceed satisfactorily with a study of glial function. Glial cells are derived embryologically from the same group ofectodermal cells that gives rise to neurons. For over one hundred years histolo- * Harvard Medical School, Boston, Massachusetts. t Harvard Medical School, Boston, Massachusetts; Fellow ofthe National Multiple Sclerosis Society . This research was supported by a grant (NB-02253-06) from the National Institutes of Health, U.S. Public Health Service. 69 gists have been able to distinguish between nerve cells and neuroglia by their different staining properties and by their general appearance. We will consider two main types of neuroglial cells in the central nervous system, the astrocytes and oligodendrocytes. These cells do not possess long processes or axons andtherefore cannot be used for signaling between distant portions ofthe organism. Unlike nerve cells, they can divide. They constitute perhaps halfthe volume ofthe vertebrate brain, and it has been estimated that glial cells outnumber neurons by a factor ofabout io to i. That we do not know what role they play, even in general terms, is a source ofembarrassment to us as neurophysiologists. Ofcourse, we assume that glial cells are functionally related to neurons. However, speculations about glial function are primarily based on histological appearances, and compelling support for our conviction is lacking. A briefsketch will illustrate the development ofa small segment ofthe ideas about the possible role ofneuroglia. The most widely held view, and probably the oldest, goes back to Golgi [?], who more than ninety years ago saw that glial cells in the brain were interposed between capillaries and neurons, apparently making intimate connections with both (see Fig. ia). He suggested, in a footnote, that glial cells serve as channels for materials moving from the blood to the neurons. Numerous other hypotheses developed , attributing to neuroglia such functions as structural supporting elements, machinery for repair and replacement when neurons are damaged or destroyed, or isolating elements separating neurons from each other. These concepts were concisely reviewed by Nageotte in 1910 [2]. A more recent comprehensive study testifies to the sturdiness ofthese ideas. In a recent book the functions ofneuroglia are listed as "connective and supporting functions. Isolation of nerve elements proper. Repair of injuries (scar formation). Transport ofmetabolic substances between blood vessels and neurons. Participation in the mechanism of blood brain barrier " [3]. Electron microscopy ofthe central nervous system gave strong support to the notion that glial cells have a role as supply routes for nutrients betweenthe bloodandneurons. Light microscopyhadindicatedthat between cells there were many open spaces filled with fluid. This fluid, usually called interstitial or intercellular fluid, was assumed to be in equilibrium with the blood plasma. In electron micrographs, however, cells were very tightly packed, mostly with narrow spaces of about 100-200 Â between 70 Stephen W. Kuffler andJohn G. Nicholls · Exchange between Blood...