Residual Bound Calcium Can Account for the Effects of Calcium Buffers on Synaptic Facilitation

V. Matveev, R. Bertram, A. Sherman

Facilitation is a transient stimulation-induced increase in synaptic response, a ubiquitous form of short-term synaptic plasticity that can regulate synaptic transmission on fast time scales. In their pioneering work, Katz and Miledi and Rahamimoff demonstrated the dependence of facilitation on presynaptic calcium influx and proposed that facilitation results from the accumulation of residual calcium bound to vesicle release triggers. However, this bound calcium hypothesis appears to contradict the evidence that facilitation is reduced by exogenous calcium buffers. This conclusion led to a widely held view that facilitation must depend solely on the accumulation of calcium in free form. Here we consider a more realistic implementation of the bound calcium mechanism, taking into account spatial diffusion of calcium, and show that a model with slow calcium unbinding steps can retain sensitivity to free residual calcium. We demonstrate that this model agrees with the facilitation accumulation time course and its biphasic decay exhibited by the crayfish inhibitor neuromuscular junction (NMJ) and relies on fewer assumptions than the most recent variants of the free residual calcium hypothesis. Further, we show that the bound calcium accumulation is consistent with Kamiya and Zucker's experimental results, which revealed that the photolytic liberation of a fast calcium buffer decreases the synaptic response within milliseconds. We conclude that calcium binding processes with slow unbinding times (tens to hundreds of milliseconds) constitute a viable mechanism of synaptic facilitation at some synapses and discuss the experimental evidence for such a mechanism.