Introduction
Ca2+ions are essential for triggering and modulating synaptic neurotransmitter release. Since most Ca2+
entering the cell is quickly bound by Ca2+ buffers, these molecules strongly shape the synaptic dynamics.
Two mechanisms have been proposed for buffer-driven short-term synaptic changes: (1) facilitation by
buffer saturation [1–3], and (2) facilitation by translocation of membrane-bound buffers into the synaptic
terminal [4].
Here, we systematically examine the impact of Ca2+buffers on the dynamics of Ca2+transients. We
focus on buffers with two Ca2+binding sites with distinct binding kinetics, characterizing buffers such as
calmodulin and calretinin, and we explore the effects of changes in buffer diffusivity upon Ca2+binding.
Methods
To explore the impact of Ca2+buffering properties on Ca2+transient dynamics, we numerically solve
reaction–diffusion equations describing the influx, diffusion, and mutual binding of Ca2+and buffer con-
centration fields in an enclosed volume simulating a single synaptic terminal. Vesicle pool dynamics are
not modeled, as we focus on synaptic plasticity effects arising solely from changes in local Ca2+transients
during a train of action potentials, upstream of additional plasticity effects due to vesicle pool depletion
and recovery. Equations are solved using the CalC (Calcium Calculator) software (GitHub: mvvik), with
wrapper code written in MATLAB (MathWorks, Inc.).
Results
Beyond facilitation via buffer saturation and dislocation, we find that strong depression of Ca2+transients
can occur in the presence of Ca2+-buffers with two binding sites, provided the second binding event is
much faster than the first. We refer to this effect as buffer priming, previously hypothesized in response
to calretinin overexpression [5]. We also demonstrate that certain buffering regimes produce complex
Ca2+dynamics, with facilitation followed by depression or vice versa. Finally, we systematically analyze
how these effects depend on binding properties and changes in buffer diffusivity through parameter sweeps.
Discussion
Although our results are based purely on computational modeling, it is valuable to systematically explore
how facilitation and depression of Ca2+transients depend on the kinetics, affinities, and mobilities of distinct
Ca2+-bound states of buffers with multiple binding sites. Such buffers are widely expressed in neurons,
yet their properties are difficult to measure. Buffer expression profiles differ across neuron classes, shaping
the synaptic dynamics. We believe this work helps elucidate the interplay between Ca2+homeostasis and
short-term synaptic dynamics, revealing the broader impact of complex buffer binding dynamics on cellular
Ca2+signaling.
References
[1] Klingauf, J., & Neher, E. (1997). Modeling buffered ca2+ diffusion near the membrane(...) Biophysical
Journal, 72 (2), 674–690.
[2] Blatow, M., Caputi, A., Burnashev, N., Monyer, H., & Rozov, A. (2003). Ca2+ buffer saturation
underlies paired pulse facilitation in calbindin(...) Neuron, 38 (1), 79–88.
[3] Matveev, V., Zucker, R., & Sherman, A. (2004). Facilitation through buffer saturation(...) Biophysical
journal, 86 (5), 2691–2709.
[4] Burnashev, N., & Rozov, A. (2005). Presynaptic ca2+ dynamics, ca2+ buffers(...) Cell calcium, 37 (5),
489–495.
[5] Bolshakov, A., Kolleker, A., Volkova, E., Valiullina-Rakhmatullina, F., Kolosov, P., & Rozov, A.
(2019). Overexpression of calretinin(...) Frontiers in Cellular Neuroscience, 13, 91.
Acknowledgement
I would like to sincerely thank my advisor, Victor Matveev, for his invaluable guidance, support, and mentorship throughout this work. It has, and will continue to be, a privilege to work with him.
