Abstracts

RATIONALE: F-actin filaments are intimately involved in both controlling dendritic spine shapes and in the attachment of glutamate receptors and interacting postsynaptic proteins. The specific disruption of F-actin filaments in dendritic spines of cultured neurons using latrunculin A results in a significant decrease in the number of synaptic AMPA and NMDA receptor clusters, and receptor re-localization to extrasynaptic sites. We have studied, for the first time in living animals, the effect of F-actin disruption on picrotoxin seizure thresholds, by perfusing latrunculin A in the rat hippocampus. METHODS: Picrotoxin seizure threshold was defined as the lower picrotoxin concentration needed to induce a seizure. Our previous studies show that picrotoxin seizure threshold remains constant in each individual rat for a period up to six months. After stablishing the seizure threshold, 20 M latrunculin A dissolved in Ringer fluid was perfused into the rat hippocampus during 8 hours using a CMA/120 microdialysis system for freely moving animals and CMA/12 microdialysis probes, with continuous EEG and videotape recording. Random control EEG recordings and a weekly threshold control were performed after latrunculin A microperfusion. RESULTS: Eight hours microperfusion of latrunculine A induced a decrease in picrotoxin seizure threshold down to 34% b6.6 of the control threshold. This effect remains for a period up to three months. However, no spontaneous seizures, interictal discharges or EEG abnormalities were observed in any of the animals during post-latrunculine controls in the absence of picrotoxin. CONCLUSIONS: Our results show that depolimeryzing F-actin filaments in vivo with latrunculin A induces long-term changes in neuronal excitability as measured by picrotoxin seizure threshold. Latrunculin A does not induce paroxysmal activity, but it facilitates somewhat the effect of picrotoxin. It is likely that these long-term changes may be due to modifications in receptor clustering or localization. (Supported by Grant XUGA 20801B97 from Xunta de Galicia, Galicia, Spain.)