ore be activated for longer period. However, autophosphorylation deepens the extend of CaMKII activation at higher frequencies and increases the competition of CaMKII with calcineurin, therefore playing a determinant role on synaptic efficacy. It has been shown that the autophosphorylation of CaMKII on Thr286 can result in bistability of enzyme activity. De Koninck et al. used in vitro experiments to demonstrate that CaMKII autophosphorylation occurs in a frequency-dependent manner and this frequency response is modulated by the amplitude and duration of each calcium pulse, which is congruent with our findings. Furthermore, repeated in vivo treatments with psychostimulants increases the surface expression of AMPA MG516 biological activity receptors in the striatum. However, paradoxically, a single cocaine injection in drug-naive animals exerts no effect on synaptic plasticity, while in drug-experienced animals it induces LTD. This may suggest a more complicated process underlying long term neuroadaptation and drugs of abuse. This model can also be adapted to understand the effect on synaptic efficacy of calcium influx through other receptors. If a sharp, high amplitude increase of free calcium reduces the requirements on high-frequency stimulation for activating CaMKII, while a moderate calcium influx requires much higher frequencies to build up, then a delayed but prolonged calcium increase induced by metabotropic glutamate receptor, especially mGluR1 and mGluR5, through activation of intracellular calcium stores, is more likely to induce LTD. A future challenge for this model will be to understand, when several mechanisms for increasing intracellular calcium concentration are simultaneously activated, the response of downstream signaling pathways. Calcium Spikes Modulate Synaptic Plasticity The computational model presented here improves our understanding of calcium signaling involved in synaptic plasticity. The frequency of postsynaptic calcium influx regulates the induction of LTP and LTD, while the amount of calcium ions shifts the windows of frequencies required for this bidirectional regulation. Besides, the availability of calmodulin and the phosphorylation on Thr286 of CaMKII not only regulate the frequency sensitivity but also the extent of CaMKII activity at high calcium frequencies. Furthermore, synaptic plasticity is induced in a cell-specific manner, and is modulated by other pathways, such as the dopamine regulated PP1 inhibition in MSN. Methods Model Structure and Validation The model encoded in the XML format used by E-Cell3 is provided as Description S1. The activation of calmodulin by calcium was modeled as described previously. In this model, calmodulin exists under two states in thermal equilibrium, the open and the close state. In either state, calmodulin can bind up to four calcium ions. Each calcium binding site is considered unique, with its own specific dissociation constants, different in the R and T states. Calmodulin can undergo transitions between R and T state, regardless of the number of calcium ions bound. Because its affinity for the R state is higher than for the T state , binding of calcium progressively lowers the free energy of the R state, facilitating the transition from T to R state. Once calmodulin is in the R conformation, it can bind to target proteins, calcineurin and CaMKII in the model, and activate them. The transient dynamics of calcium association and dissociation with calmodulin was justified by stopped-flow flu