Structural specialization of mossy fiber boutons is necessary for their unique computational functions

Abstract

Sparsely active granule cells in the dentate gyrus (DG) project onto CA3 pyramidal neurons through mossy fibers (MF), forming a feedforward network that ensures even similar inputs activate distinct and minimally overlapping populations of CA3 neurons. This process, known as pattern separation, is a key computational feature at this synapse. However, such sparse activity and connectivity increase the risk of information loss, as multiple presynaptic inputs are typically required to elicit a postsynaptic action potential. Interestingly, MF synapses exhibit robust short-term plasticity (STP), enabling a dynamic increase in release probability during brief bursts of presynaptic activity. This mechanism ensures that a short, high-frequency burst from a single granule cell can reliably generate a spike in its postsynaptic CA3 target. Unlike other hippocampal synapses, MF boutons are large, with multiple active zones, each coupled to a cluster of voltage-dependent calcium channels (VDCCs). MF boutons also possess a large readily releasable pool of vesicles. The functional consequences of this unusual synaptic design remain largely unexplored. In fact, the MF synapse is often depicted as a synapse with multiple sites, each behaving as an independent transmission line, analogous to several CA3 boutons contacting a single CA1 dendrite. We developed a physiologically realistic spatial model of the MF bouton to investigate how its peculiar structural and functional properties affect synaptic signaling and plasticity. Contrary to earlier assumptions, our computational model revealed, release sites are not independent transmission units. Crosstalk between calcium domains is necessary for the observed strong STP and for the timely activation of CA3 neurons. VDCCs in the MF bouton are only loosely coupled to active zones, and the distance between active zones is relatively large. In addition to the synaptic design and the known role of calbindin-D28k and synaptotagmin-7 in STP, we find that loose coupling of VDCCs to active zones and large inter-AZ distances are crucial. These features keep the basal release probability low, and their combined action is required to generate the facilitation that triggers postsynaptic action potentials in response to bursts filtering out non-informative dentate activity, and provides a strong rationale for the mossy fibers synaptic architecture.