Nonsynaptic mechanisms exert a powerful influence on seizure threshold. It is well-established that nonsynaptic epileptiform activity can be induced in hippocampal slices by reducing extracellular Ca(2+) concentration. We show here that nonsynaptic epileptiform activity can be readily induced in vitro in normal (2 mM) Ca(2+) levels. Those conditions sufficient for nonsynaptic epileptogenesis in the CA1 region were determined by pharmacologically mimicking the effects of Ca(2+) reduction in normal Ca(2+) levels. Increasing neuronal excitability, by removing extracellular Mg(2+) and increasing extracellular K(+) (6-15 mM), induced epileptiform activity that was suppressed by postsynaptic receptor antagonists [D-(-)-2-amino-5-phosphonopentanoic acid, picrotoxin, and 6,7-dinitroquinoxaline-2,3-dione] and was therefore synaptic in nature. Similarly, epileptiform activity induced when neuronal excitability was increased in the presence of K(Ca) antagonists (verruculogen, charybdotoxin, norepinephrine, tetraethylammonium salt, and Ba(2+)) was found to be synaptic in nature. Decreases in osmolarity also failed to induce nonsynaptic epileptiform activity in the CA1 region. However, increasing neuronal excitability (by removing extracellular Mg(2+) and increasing extracellular K(+)) in the presence of Cd(2+), a nonselective Ca(2+) channel antagonist, or veratridine, a persistent sodium conductance enhancer, induced spontaneous nonsynaptic epileptiform activity in vitro. Both novel models were characterized using intracellular and ion-selective electrodes. The results of this study suggest that reducing extracellular Ca(2+) facilitates bursting by increasing neuronal excitability and inhibiting Ca(2+) influx, which might, in turn, enhance a persistent sodium conductance. Furthermore, these data show that nonsynaptic mechanisms can contribute to epileptiform activity in normal Ca(2+) levels.