Publication Type:Journal Article
Source:Proceedings of the National Academy of Sciences (2018)
Neurons fire action potentials to transfer information through synaptic release of neurotransmitter. At presynaptic terminals, the pattern of action potential discharge is integrated through dynamic Ca2+ signaling by the presynaptic machinery which triggers the release of neurotransmitter. It is generally accepted that the rate and the temporal precision of action potential firing support information transfer between neurons. Here, we show that in contrast to rate and temporal coding, giant mossy fiber terminals count the number of action potentials during trains to trigger CA3 pyramidal cell firing. Our results shed light on the synaptic signal transfer mechanisms supporting an additional information coding strategy in the brain.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. However, the spiking patterns required to trigger action potential firing in CA3 pyramidal neurons remain poorly understood. 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 rapid Ca2+ imaging we also show that the magnitude of evoked Ca2+ influx stays constant during action potential trains and that accumulated residual Ca2+ is gradually extruded on a time scale of several hundred milliseconds. Using experimentally constrained 3D 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. This is largely determined by the differential contribution of major endogenous Ca2+ buffers calbindin-D28K and calmodulin and by the loose coupling between presynaptic voltage-gated Ca2+ channels and release sensors and the relatively slow Ca2+ extrusion rate. Taken together, our results identify a previously unexplored information-coding mechanism in the brain.