Title: “Action potential counting at giant mossy fiber”

Neuronal communication relies on action potential discharge, with the frequency and the temporal precision of action potentials encoding information. Hippocampal mossy fibers have long been recognized as conditional detonators owing to prominent short-term facilitation of glutamate release displayed during granule cell burst firing. Here, we show that glutamate release from mossy fiber terminals triggers action potential firing of the target CA3 pyramidal neurons independently of the average granule cell burst frequency, a phenomenon we term action potential counting. We find that action potential counting in mossy fibers gates glutamate release over a broad physiological range of frequencies and action potential numbers. Using experimentally-constrained three-dimensional model of presynaptic Ca2+ influx, buffering and diffusion, and a Monte Carlo model of Ca2+-activated vesicle fusion we argue that action potential counting at mossy fiber boutons can be explained by a unique interplay between Ca2+ dynamics and buffering at release sites. Taken together our results identify a previously unexplored information coding mechanism in the brain.