Until recently, the only means by which electrical activity was believed to initiate retrograde signals was via postsynaptic events: modulated synthesis or release of trophic factors. We have evidence in chick embryos for a presynaptic initiation of retrograde signals from the retina to the isthmo-optic nucleus, which is known to undergo 55% neuron death between embryonic days 12 and 17 and to become laminated during this period. Intraocular injections of saxitoxin just before embryonic day 14 reduce neuron death and prevent lamination in the isthmo-optic nucleus within as few as 6 hr. We show that these rapid effects are attributable to the direct action of saxitoxin on the isthmo-optic terminals. Alternative possibilities, such as an indirect effect via the target cells, are ruled out by control experiments. Normally, action potentials may lead to a chain of second messenger events in the axon terminal that is signaled retrogradely via the transport of a long-lived second messenger.