Intracellular and extracellular recordings were made from human neocortical slices of the temporal lobe maintained in vitro. The slices were treated with bicuculline methiodide to reduce synaptic inhibition mediated by tha gamma-aminobutyric acid A (GABAA) receptor. Spontaneously occurring epileptiform activity was never observed in over 60 slices examined. All epileptiform discharges were elicited by single-shock stimuli delivered in the underlying white matter or within the cortical layers. Intracellularly, the stimulus-induced epileptiform discharge resembled the paroxysmal depolarization shift (PDS). This potential was observed in neurons located between 200 and 2200 microns from the pia. It was characterized by a 100-1800 ms long depolarization which triggered burst firing of action potentials, and was at times followed by an afterdischarge. Simultaneous intracellular and extracellular recordings showed that each PDS was reflected by the synchronous discharge of a neuronal aggregate. The voltage behaviour of the PDS and its preceding EPSP was analyzed in cells that were injected with the lidocaine derivative QX-314. The amplitudes of the PDS depolarizing envelope measured at its peak and during its falling phase both behaved as a monotonic function of the membrane potential by increasing in amplitude during hyperpolarization. In addition, the PDS peak amplitude showed a much greater rate of increase than the early EPSP peak amplitude, thus suggesting that the synaptic conductance underlying the PDS was much greater. Perfusion of the neocortical slices with the N-Methyl-D-aspartate (NMDA) receptor antagonist DL-2-amino-phosphonovaleric acid (APV) reduced both the duration and the amplitude of the paroxysmal field discharge in a dose related fashion. The effects of APV were reflected intracellularly by an attenuation of the PDS's late phase and a blockade of the afterdischarge. Similar findings were also obtained by using the NMDA receptor antagonist 3-((+-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid. These data indicate that reduction or blockade of the GABAA receptor is sufficient to elicit epileptiform discharges in the human neocortex maintained in vitro. Mechanisms dependent upon the NMDA receptor contribute to this type of epileptiform response mainly by prolonging the stimulus-induced depolarizing potential and the associated burst of firing.