. Contribution of individual spikes in burst-induced long-term synaptic modification. J Neurophysiol 95: 1620 -1629, 2006. First published November 30, 2005 doi:10.1152/jn.00910.2005. Longterm synaptic modification depends on the relative timing of individual pre-and postsynaptic spikes, but the rules governing the effects of multispike bursts remain to be fully understood. In particular, some studies suggest that the spike timing dependence of synaptic modification breaks down with high-frequency bursts. In this study, we characterized the effects of pre-and postsynaptic bursts on long-term modification of layer 2/3 synapses in visual cortical slices from young rats. We found that, while pairing-induced synaptic modification depends on the burst frequency, this dependence can be explained in terms of the timing of individual pre-and postsynaptic spikes. Later spikes in each burst are less effective in synaptic modification, but spike efficacy is regulated differently in pre-and postsynaptic bursts. Presynaptically, spike efficacy is progressively weakened, in parallel with short-term synaptic depression. Postsynaptically, spike efficacy is suppressed to a lesser extent, and it depends on postsynaptic potassium channel activation. Such timing-dependent interaction among multiple spikes can account for synaptic modifications induced by a variety of spike trains, including the frequency-dependent transition from depression to potentiation induced by a postsynaptic burst preceding a presynaptic burst.