1. Measurements have been made of the extraneuronal potential changes produced by replacement of sodium ions with other organic and inorganic cations in the solution bathing isolated abdominal connectives.
2. On the basis of the observed extraneuronal potential changes it is possible to arrange monovalent cations in the following sequence of effectiveness:
K+ > Rb+ > Cs+ > TEA+ > Na+ > Li+ > choline+ > tris+.
3. It is concluded that the ionic dependence of the extraneuronal potentials is similar to that of a theoretical model system consisting of a perineurial diffusion barrier in series with a long, narrow channel representing the system of intercellular clefts connecting the inwardly facing surface of the perineurium with the extraaxonal fluid.
4. On the basis of this model the effect of high external concentrations of, for example, potassium ions would be to depolarize the outwardly facing perineurial cell membranes. The considerable departure of the observed potentials from the values predicted by the Nernst equation can be accounted for in terms of the short-circuiting effect, due to the finite ionic permeability of the tight junctions between perineurial cells. Qualitative predictions can also be made concerning the rates of movement of potassium and sodium ions in the extracellular system.