Activity–dependent plasticity including short and long-term depression accompanied by a reduction in transmitter release probability has been demonstrated in both inhibitory and excitatory synapses. In the neonatal hippocampus, repetitive postsynaptic depolarization is followed by presynaptic alterations of the efficacy of GABAAergic transmission. Both facilitation and inhibition have been observed, but the mechanisms underlying this plasticity have not yet been elucidated. In the present experiment, repetitive postsynaptic depolarization by itself did not cause marked alterations of spontaneous inhibitory postsynaptic currents (sIPSCs). Activation of presynaptic neurons by increasing extracellular K+ concentration ([K+]o) temporarily induced facilitation of sIPSCs, but successive repetitive depolarizations transiently reduced the current frequency. This newly discovered inhibition was expressed presynaptically, could not be induced by postsynaptic depolarization alone, and was facilitated by the activation of NMDA receptors. IPSC inhibition was suppressed using the antagonists of metabotropic glutamate receptors (mGluRs) or muscarinic ACh receptors (mAChRs). Furthermore, transient inhibition was reduced by an antagonist of the type 1 cannabinoid receptor (CB1 receptor). The effect of CB1 receptor agonist on the sIPSCs was potentiated by [K+]o elevation, implying a role for the [K+]o elevation other than the release of transmitters. These results show that weak postsynaptic activation, when combined with presynaptic activation, leads to an inhibition of GABAergic synapses in the neonatal hippocampus. This inhibition is mediated by a mechanism involving mGluRs, mAChRs, and CB1 receptors, and potentiated by NMDA receptor activation.