The hippocampal formation contains a variety of neuronal types. The principal neurons are granule cells in the dentate gyrus and pyramidal cells in Ammon's horn. These two neuron types show distinct cell morphology and display a different vulnerability to ischemic injury or various neurotoxins. In order to illustrate the difference in the pathophysiological properties of these neurons, we established a method for separately culturing granule cells and pyramidal cells. They were prepared from the dentate gyrus and Ammon's horn of 3-day-old Wistar rat pups and maintained for 7-9 days in culture. After transient exposure to N-methyl-D-aspartate or glutamate, both the cultured neuron populations displayed somatic Ca(2+) transients with similar amplitudes, but the subsequent recovery to baseline was about twice as fast in granule cells than in pyramidal cells. Similar results were obtained for K(+) depolarization-induced Ca(2+) elevation, suggesting that the relatively rapid Ca(2+) clearance in granule cells is independent of Ca(2+) influx pathways. The present study provides the first evidence for a difference in Ca(2+) dynamics and homeostasis between granule and pyramidal cells and may represent a cellular basis for the differential vulnerability of hippocampal neurons.