The mechanisms by which cerebral ischemia and several neurotoxins cause regionally selective damages to the hippocampal formation are largely unknown. The CA1-selective toxicity of N-methyl--aspartate (NMDA), the CA3-selective toxicity of kainate, and the dentate gyrus (DG)-selective toxicity of colchicine were observed in organotypic entorhino-hippocampal cultures. The selective neurotoxicity of NMDA and colchicine but not kainate was present in isolated tissue cultures of each hippocampal subregion, suggesting that the regional vulnerability is irrespective of the hippocampal trisynaptic pathway. Dispersed cultures of neurons prepared from Ammon's horn and the DG still exhibited a preference for susceptibility to NMDA and colchicine, respectively. Thus, the neurons per se appear to be inherently susceptible to specific toxins independently of their original loci, intrinsic neural circuits, vascular system, or other systemic factors.