Dendritic calcium (Ca) spikes play a key role in the genesis of long-term synaptic plasticity. Although synaptic plasticity in the infralimbic cortex is critical for the extinction of fear conditioned memory, the role of Ca-spikes in the induction of synaptic plasticity at this cortex has not been explored in depth. Here we show that Ca-spikes in layer 5 pyramidal neurons (L5 PNs) of the rat infralimbic cortex are crucial in the induction of long-term depression of the excitatory postsynaptic currents (EPSCs). The lack of effect on the postsynaptic currents evoked by puffing glutamate and the changes in the variance of the EPSC amplitude that paralleled its inhibition suggest that this LTD of the EPSCs is mediated presynaptically. However, its induction requires cytosolic calcium elevations because it is prevented when the recorded L5 PN is loaded with BAPTA. Moreover, it depends on the synthesis of nitric oxide (NO) because it is absent on slices incubated with nitric oxidase synthase inhibitor L-NAME. Therefore, Ca-spikes can trigger LTD of the ESPCs through the NO dependent presynaptic form of synaptic plasticity, thus providing a novel form of inducing synaptic plasticity at L5 PNs of the rat infralimbic cortex.