Ca²⁺buffering as a mechanism of short-term synaptic plasticity

Spatio-temporal compartmentalization allows Ca²⁺ signals to simultaneously regulate multiple vital cell processes and relies in part on Ca²⁺ buffers that absorb at least 98% of Ca²⁺ ions entering the cytoplasm. Computational modeling has played a central role in the understanding of localized Ca²⁺ signals in neurons and other cell types. Although many models consider only simple, one-to-one Ca²⁺ buffering stoichiometry, practically all buffers have multiple Ca²⁺ binding sites which often display cooperative binding (e.g., calretinin [1–3], calmodulin [4, 5] ). Given the simplest case of two binding sites, cooperativity manifests itself in an order of magnitude difference in the binding and/or unbinding rates of the two consecutive Ca²⁺ binding steps in the following buffer reaction:

Here we extend recent modeling studies of cooperative buffering [1–5], and find that it can lead to spatio-temporal Ca²⁺ signals that cannot be achieved by any combination of non-cooperative buffers, in particular during a sequence of action potentials or synaptic inputs. Namely, Figure 1B shows that cooperative Ca²⁺ buffering can potentially serve as a mechanism of short-term synaptic depression, in contrast to the case of non-cooperative buffers (Figure 1A), which are believed to underlie short-term synaptic facilitation in certain types of mammalian synapses [6, 7].

Figure 1

[Ca²⁺] elevation during a 40 Hz train of 1ms-long Ca²⁺ pulses at 100nm from the Ca²⁺ source. A: In the presence of a non-cooperative buffer, Ca²⁺ transients facilitate due to gradual depletion (saturation) of free buffer [6, 7]. B: In the presence of a cooperative buffer, Ca²⁺ transients depress as a result of increasing exposure of the high-affinity Ca²⁺ binding site. Both simulations done in 1D geometry (0.5 μm axonal segment), computed using CalC version 7.2 (http://www.calciumcalculator.org)

We explore this phenomenon in detail, demonstrating the dependence of such buffer-induced short-term synaptic plasticity on all relevant buffering parameters. These results may lead to better understanding of post-synaptic Ca²⁺ dynamics as well, yielding a deeper insight into synaptic transmission and its dynamic regulation, and may also have relevance for Ca²⁺-dependent processes in other cells such as endocrine cells, myocytes and immune system cells.