We have studied the synaptic responses in hippocampal slices to stimulus patterns derived from in vivo recordings of place cell firing in a behaving rodent. We find that synaptic strength is strongly modulated during the presentation of these natural stimulus trains, varying 2-fold or more because of short-term plasticity. This modulation of synaptic strength is precise and deterministic, because the pattern of synaptic response amplitudes is nearly identical from one presentation of the train to the next. The mechanism of synaptic modulation is primarily a change in release probability rather than a change in the size of the elementary postsynaptic response. In addition, natural stimulus trains are effective in inducing long-term potentiation (LTP). We conclude that short-term synaptic plasticity-facilitation, augmentation, and depression-plays a prominent role in normal synaptic function.