The contribution of non-synaptic mechanisms to the seizure susceptibility of rat CA1 hippocampal pyramidal cells was examined in vitro by testing the effects of osmolality on synchronous neuronal activity, using solutions which blocked chemical synaptic transmission both pre- and post-synaptically. Decreases in osmolality, which shrink the extracellular volume, caused or enhanced epileptiform bursting. Increases in osmolality with membrane-impermeant solutes, which expand the extracellular volume, blocked or greatly reduced epileptiform discharges. Reductions in the extracellular volume, therefore, can enhance synchronization among CA1 hippocampal neurons through non-synaptic mechanisms. Since similar osmotic treatments are known to modify epileptiform discharges in several models of epilepsy, non-synaptic mechanisms are probably more important in hippocampal epileptogenesis than previously realized and may contribute to the high susceptibility of this brain region to epileptic seizures in animals and humans. These data also provide a possible explanation for the observation in humans that decreased plasma osmolality, which can be associated with a wide range of clinical syndromes, leads to seizures.