We describe here the ionic changes which occur during repetitive stimulation of a type which will induce long-term potentiation and kindling plasticity. The causes of these ionic changes, particularly of changes in [Ca2+]o, are discussed. Evidence will be presented which shows that only a fraction of the decreases in [Ca2+]o is due to movement through N-methyl-D-aspartate (NMDA)-operated channels. Since NMDA-receptor activation is critical in many synapses for induction of long-term potentiation (LTP) and since the initial response to a stimulus in hippocampus is a long-lasting slow inhibitory postsynaptic potential (IPSP), mechanisms must be defined which ultimately permit activation of NMDA receptors. We conclude that increases in [K+]o and reductions in [Ca2+]o and [Mg2+]o, together with a K(+)-dependent reduction of slow IPSP promote the activation of NMDA receptors during a stimulus train and help to overcome the blocking effect which the long-lasting hyperpolarizations exert on NMDA receptors. Preliminary evidence derived from analysis of quisqualate and NMDA-induced changes in [Ca2+]o suggests that NMDA-receptor activation slows the extrusion of Ca2+ from cells. This mechanism may be important for induction of long-term changes. Finally, we document that a number of long-term changes in neuronal excitability are associated with alterations of stimulus and excitatory amino acid (EAA)-induced changes in the ionic microenvironment, which give some insight into the mechanisms underlying stimulus-induced plasticity and, perhaps, progression of temporal lobe epilepsy.