Acute osmotic disturbances can lead to profound neurological problems, yet there has been little experimentation at a cellular level to assess if neurophysiological changes are induced by altered osmolality. Using extra- and intracellular recording in the rat neocortical slice preparation, we examined pyramidal neurons of layers II-III under changing osmotic conditions. Single cell properties, field potentials, synaptic transmission and epileptiform discharges were studied in control saline (295 mOsm) and compared with corresponding data collected during exposure to osmolalities between 245 and 375 mOsm. Single cell properties (resting membrane potential, cell input resistance, action potential threshold and duration) did not change significantly, but neuronal interactions were considerably influenced by osmotic change within minutes. Hyposmolality increased the amplitude of evoked field potentials and of excitatory postsynaptic potentials recorded intracellularly. Hyperosmolality, induced with mannitol, decreased these parameters. Electrotonic coupling, as gauged by the degree of dye coupling and by cell input resistance, was not influenced by shifts in osmolality. The clinical finding that overhydration promotes seizure onset was examined in slices made epileptogenic in Mg2(+)-free saline. Hyposmolality increased the frequency and decreased the duration of interictal bursts, whereas raising osmolality with mannitol had opposite effects. None of the aforementioned effects occurred when osmolality was increased with a freely permeable substance such as dimethylsulfoxide, nor could they be ascribed to changes in saline Na+ or Ca2+ concentrations. The results are consistent with hyposmotic solutions reducing extracellular space by causing cells to swell. Theoretically, during population discharge, this should both concentrate K+ released extracellularly and possibly increase field (ephaptic) interactions. How lowered osmolality strengthens spontaneous and evoked excitatory synaptic transmission in neocortex is not yet clear. However, it may be an important mechanism underlying the increased seizure susceptibility of patients and experimental animals with lowered plasma osmolality. Conversely, suppression of excitatory postsynaptic potentials by osmotically active substances may be involved in the lowered seizure susceptibility observed clinically.