In standard protocols, the frequency of synaptic stimulation determines whether CA1 hippocampal synapses undergo long-term potentiation or depression. Here we show that during cholinergically induced theta oscillation (theta) synaptic plasticity is greatly sensitized and can be induced by a single burst (4 pulses, 100 Hz). A burst given at the peak of theta induces homosynaptic LTP; the same burst at a trough induces homosynaptic LTD of previously potentiated synapses. Heterosynaptic LTD is produced at inactive synapses when others undergo LTP. The synaptic modifications during theta require NMDA receptors and muscarinic receptors. The enhancement is cooperative and occludes with standard LTP. These results suggest that the similar bursts observed during theta rhythm in vivo may be a natural stimulus for inducing LTP/LTD.