CNS*2026 Halifax

Introduction


The mossy Fiber Bouton (MFB) in hippocampus acts as a detonator synapse with sophisticated morphology, large number of vesicles and multiple active zones (AZs), which provide the physical basis for the detonator properties [1]. However, how presynaptic MFB terminals decode the frequency and number of action potentials to transmit information remains poorly understood.  Due to its complicated morphology, by far there has been no detailed simulation on the presynaptic neurotransmission in a realistic MFB morphology.

Methods


Here, we utilize experimental 3D electron microscopic (EM) data from our collaborators of Prof. Dr. Joachim Lübke unit in Juelich Germany to investigate the basic mechanism of how vesicle docking and release machinery within complicated morphology contributes to MFB’s detonator property. Based on the detailed kinetics of vesicle docking process and rich distribution of mitochondria for uptake calcium in MFB, by implementing the calcium sensor synaptotagmin 1(syt1) and synaptotagmin 7 (syt7) into the exocytosis machinery, we simulate the presynaptic vesicle release of MFB by STochastic Engine for Pathway Stimulation (STEPS)(https://steps.sourceforge.net/manual/) [2,3].

Results


Our results show that surprisingly, all the eight morphologically distinct MFBs consistently exhibit the detonator properties, despite the diversity and variety of vesicle number, bouton size, AZ distributions from each bouton. MFB boutons exhibit frequency independent neural transmission with fast vesicle docking mechanism (spike counting strategies). The release event per pulse highly depends on calcium channel density yet did not change the intrinsic Short Time Facilitation (STF) feature.  Active transport of vesicles can facilitate the fast vesicle docking in some boutons enhancing the detonator properties; for other boutons, active transport did not show difference from pure diffusion probably due to the high density of vesicles.

Discussion


Importantly, our results demonstrate that in certain bouton uptake of calcium by mitochondria plays an important role in regulating precise signal transduction, while for other bouton the effect is not so obvious, though mitochondria still play a role in regulating calcium homeostasis. Finally, we show that spike-locked synchronous release by syt1 dominate over occasional asynchronous releases by syt7, which is consistent to experimental results. In conclusion, a STEPS model of neural transmission in giant MFB with realistic morphology and molecular details provides insights of why MFBs show detonator properties.

References


[1] Nicoll, R. A., & Schmitz, D. (2005). Synaptic plasticity at hippocampal mossy fibre synapses. Nature Reviews Neuroscience, 6(11), 863–876. https://doi.org/10.1038/nrn1786
[2] Gallimore, A. R., Hepburn, I., Georgiev, S. V., Rizzoli, S. O., & De Schutter, E. (2025). Dynamic regulation of vesicle pools in a detailed spatial model of the complete synaptic vesicle cycle. Science Advances, 11(22), eadq6477. https://doi.org/10.1126/sciadv.adq6477
[3] Hepburn, I., Lallouette, J., Chen, W., Gallimore, A. R., Nagasawa-Soeda, S. Y., & De Schutter, E. (2024). Vesicle and reaction-diffusion hybrid modeling with STEPS. Communications Biology, 7(1), 573. https://doi.org/10.1038/s42003-024-06276-5

Acknowledgement


We thank our collaborator Prof. Dr. Joachim H. R. Lübke from Juelich Germany to kindly provide EM data of MFB: Rollenhagen, A., Sätzler, K., Rodríguez, E. P., Jonas, P., Frotscher, M., & Lübke, J. H. R. (2007). Structural Determinants of Transmission at Large Hippocampal Mossy Fiber Synapses. The Journal of Neuroscience, 27(39), 10434–10444. https://doi.org/10.1523/JNEUROSCI.1946-07.2007.