In recent physiological experiments focusing on synaptic plasticity, it is shown that synaptic modifications induced at one synapse are accompanied by hetero-synaptic changes at neighbor sites (Bi, 2002). These evidences imply that the hetero-synaptic interaction plays an important role in reconfiguration of synaptic connections to form and maintain functional neural circuits. Here, according to some physiological studies, we hypothesized that the hetero-synaptic interaction was based on the intracellular calcium signaling, which is regulated by interactions between NMDA receptors (NMDARs), voltage-dependent calcium channels (VDCCs) and Ryanodine receptors (RyRs) on endoplasmic reticulum (ER). We simulated intracellular calcium dynamics at a cellular level, using the computational neuron model (Keizer and Levine, 1996; Poirazi et al., 2003). Using the proposed model, we induced calcium influxes at a local site in postsynaptic dendrite by controlling the spike timings of pre- and postsynaptic neurons. As a result, synchronized calcium influxes through NMDARs and VDCCs caused calcium release from ER. According to the phase plane analysis, RyR-mediated calcium release occurred when the calcium concentration in cytoplasm sufficiently increased under the condition of a high calcium concentration in ER. An NMDAR-mediated calcium influx was slow and persistent, consequently responsible for maintaining a high calcium concentration in ER. In contrast, a VDCC-mediated calcium influx was rapid and transient so that it contributed to rapid increase in calcium the concentration in cytoplasm. Taken together, it was found that cytoplasmic calcium concentration exhibited a supralinear increase when a presynaptic spike preceded a postsynaptic one. The calcium ions released from ER diffused along cytoplasm and activated RyRs at neighboring sites. The range of calcium propagation produced by the chain activation of RyRs depended on dendritic locations. According to the experimental evidences that the outcome of synaptic plasticity depends on postsynaptic calcium concentration, it was suggested that the RyR-regulated calcium propagation could serve as the mechanism of the hetero-synaptic interaction.