DISTINCT EFFECTS OF CLOSTRIDIAL TOXINS ON ACTIVITY-DEPENDENT MODULATION OF AUTAPTIC RESPONSES IN CULTURED HIPPOCAMPAL-NEURONS

Clostridial neurotoxins proteolyse specific proteins implicated in syn aptic vesicle exocytosis, but their actions on the release machinery i n functional synapses is not well understood. Here we examine the effe cts of botulinum toxin A (BoNT/A) and tetanus toxin (TeTx) on autaptic transmission in cultured rat hippocampal neurons using whole-cell vol tage clamp recordings. The proportion of cells responding to stimulati on with an excitatory postsynaptic current (EPSC) and the magnitude of the remaining responses decreased gradually with increasing concentra tion of either toxin. However, the activity-dependent modulation (5 Hz repetitive stimulation) of EPSCs remaining after toxin inhibition dif fered markedly between the two toxins. The TeTx inhibition was associa ted with a persistent activity-dependent depression similar to that in control cells, In contrast, the BoNT/A inhibition was accompanied by a reversal of the modulation into facilitation, resembling that induce d by lowering of the calcium concentration. These results demonstrate a difference between BoNT/A and TeTx in their mode of inhibition of sy naptic Vesicle exocytosis, which suggests that they exert their prefer ential actions at distinct steps of the release process.