Extracellular transport of molecules is slowed down by tissue hindrance that is defined by the tortuosity, λ = (D/D*)0.5, where D is the free diffusion coefficient and D* is the effective diffusion coefficient in tissue (Nicholson 2001, Rep Prog Phys 64:815). In cartilage or capillary glycocalyx, there is a pronounced charge-based interaction between transported molecules and the extracellular environment, manifested in λ (Maroudas 1970, Biophys J 10:365; Stace & Damiano 2001, Biophys J 80:1670). In cerebellum, however, monovalent anions and cations are hindered equally (Nicholson & Phillips 1981, J Physiol 321:225). We recently found that λ measured in the stratum radiatum of hippocampal CA1 region with tetramethylammonium (TMA+, MW 74) was 1.47 but only 1.29 when divalent anion Lucifer Yellow (LY2-, MW 457) was employed (Hrabetova et al. 2003, SFN Program No. 477.8). We hypothesize that the transport of divalent, but not monovalent, ions in brain is governed by charge-based discrimination. To test this w...