Cytoskeleton disruption causes apoptotic degeneration of dentate granule cells in hippocampal slice cultures

Colchicine, a potent microtubule-depolymerizing agent, is well known to selectively kill dentate granule cells in the hippocampal formation in vivo. Using organotypic Cultures of rat entorhino-hippocampal slices, we confirmed that in vitro exposure to 1 muM and 10 muM of colchicine reproduced a specific degeneration of the granule cells alter 24 h. Similar results were obtained with other types of microtubule-disrupting agents, i.e., nocodazole, vinblastine, and Taxol. Interestingly, the actin-depolymerizing agents cytochalasin D and latrunculin A also elicited selective neurotoxicity in the dentate gyros without affecting survival of hippocampal pyramidal cells. The selective pattern of degeneration was observable 24 h after a brief treatment with the toxins as short as 5 min, but this delayed neuronal death was unlikely to be a result of excitotoxicity because it was Virtually unaffected by glutamate receptor antagonists, tetrodotoxin, or extracellular Ca2+-free conditions. The damaged tissues contained a large number of TUNEL-positive neurons and exhibited an increased level in caspase-3-like activity, Suggesting that cytoskeleton disruption triggers an apoptosis-like process in dentate granule cells. Thus, this study may provide a basis for understanding the distinctive mechanism that Supports granule cell survival. (C) 2002 Published by Elsevier Science Ltd.