We investigated extracellular slow negative transient in dentate granule cells of human epileptic hippocampus. Hippocampal slices were prepared from brain specimens removed from 23 patients who underwent surgical treatment for medically intractable seizures. In 15 patients, hippocampi were sclerotic and the aberrant anatomical reorganization of dentate granule cell axons (mossy fibers) was detected. In eight patients, hippocampi were non-sclerotic and nominal reorganization was detected. Single perforant path stimulation evoked field responses in dentate granule cells in all 23 hippocampi. In sclerotic hippocampi, evoked field responses were followed by a slow onset extracellularly negative potential, which appeared gradually in the course of low frequency stimulation of the perforant path. Single action potentials could be recorded from negative potentials indicating that these potentials represented dentate granule cell depolarization. A low concentration of bicuculline methiodide (10 microM), a GABAA receptor antagonist, facilitated the appearance of negative potentials suggesting that a reduction in functional inhibition could unmask these potentials. The application of D-2 amino-5-phosphonovaleric acid blocked extracellular negative potentials, but initial perforant path responses were spared. This finding suggested that negative potentials were at least in part mediated by the N-methyl-D-aspartate receptor subtypes in their generation. In contrast, in non-sclerotic hippocampi with nominal "reorganization", no extracellular negative potentials were observed. The present study suggests that dentate granule cell excitability could be amplified when their reorganized axonal pathways were present in human sclerotic hippocampus as previously proposed in animal models of epilepsy.