Spike time-dependent plasticity (STDP) consists in bi-directional modifications of synaptic strength occurring by pairing pre and postsynaptic spiking. At immature GABAergic mossy fibers (MF)-CA3 synapses, STDP is characterized by a weakening of synaptic strength regardless of the temporal order of stimulation (pre versus post or viceversa). STD-LTD induced by positive pairing could be shifted into STD-LTP after blocking presynaptic GluK1 kainate receptors (KARs), indicating that KARs activated by "ambient" glutamate control the direction of STDP. STD-LTD caused by negative pairing was unaffected by KARs but was prevented by the CB1 antagonist AM251. In the absence of AM251, the mean peak amplitude of MF-evoked GABA_A-mediated postsynaptic currents (GPSCs) was 80.5 ± 12.6 pA and 41.6 ± 9.7 pA before and after pairing, respectively (n = 29; p < 0.001). This effect was presynaptic in origin because it was associated with a decrease in the number of successes, of CV^-2 and an increase in the paired pulse ratio. To further assess whether STD-LTD was dependent on the activation of CB1 receptors, similar experiments were performed on WT-littermates and CB1 -/- mice. While in WT mice the pairing protocol produced as in rats a persistent depression of MF-GPSCs (59.2 %± 4.5 %; n=9; p=0.003), in -/- mice no depression was detected (100.8 %± 3.6 %; n=10; p=0.3). These experiments strongly indicate that at immature MF-CA3 synapses STD-LTD is mediated by CB1 receptors.