Several reports have implicated the overactivity of hippocampal glutaminergic systems in neurodegenerative conditions including Senile dementia of the Alzheimer's type (SDAT). The neurobiological effects of hippocampal glutaminergic hyperactivity were studied by perforant pathway stimulation. Forty-five minutes of sustained perforant pathway stimulation produced a 50% or greater increase in motor activity 1, 2, and 3 weeks after stimulation. Robust retention deficits in a 48-h step-through passive avoidance task were evident 2 weeks post-stimulation. Furthermore, animals receiving stimulation were impaired in the acquisition of a spatial task in the Morris water maze. Stimulated animals exhibited little reduction in their escape latencies over the testing period. The learning and memory deficits were associated with a loss of CA1 and CA3 pyramidal cells and pretreatment with the N-methyl-D-aspartate antagonist MK-801 reduced this cell loss, particularly in the CA1 region of the hippocampus. These results suggest that sustained stimulation of the perforant pathway may be useful in studying neurological deficits associated with glutaminergic hyperfunction.