期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：34
DOI：10.1073/pnas.2207987119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Central nervous system synapses are diverse in strength and plasticity. Short-term plasticity has traditionally been evaluated with models postulating a single pool of functionally homogeneous fusion-competent synaptic vesicles. Many observations are not easily explainable by such simple models. We established and experimentally validated a scheme of synaptic vesicle priming consisting of two sequential and reversible steps of release–machinery assembly. This sequential two-step priming scheme faithfully reproduced plasticity at a glutamatergic model synapse. The proposed priming and fusion scheme was consistent with the measured mean responses and with the experimentally observed heterogeneity between synapses. Vesicle fusion probability was found to be relatively uniform among synapses, while the priming equilibrium at rest of mature versus immature vesicle priming states differed greatly.
Glutamatergic synapses display variable strength and diverse short-term plasticity (STP), even for a given type of connection. Using nonnegative tensor factorization and conventional state modeling, we demonstrate that a kinetic scheme consisting of two sequential and reversible steps of release–machinery assembly and a final step of synaptic vesicle (SV) fusion reproduces STP and its diversity among synapses. Analyzing transmission at the calyx of Held synapses reveals that differences in synaptic strength and STP are not primarily caused by variable fusion probability (
p
fusion
) but are determined by the fraction of docked synaptic vesicles equipped with a mature release machinery. Our simulations show that traditional quantal analysis methods do not necessarily report
p
fusion
of SVs with a mature release machinery but reflect both
p
fusion
and the distribution between mature and immature priming states at rest. Thus, the approach holds promise for a better mechanistic dissection of the roles of presynaptic proteins in the sequence of SV docking, two-step priming, and fusion. It suggests a mechanism for activity-induced redistribution of synaptic efficacy.
关键词：ensynaptic transmissionshort-term plasticitysynaptic vesicle primingcalyx of Heldnumerical simulation
