A sequential two-step priming scheme reproduces diversity in synaptic strength and short-term plasticity

Abstract

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.

Presynaptic Rac1 controls synaptic strength through the regulation of synaptic vesicle priming

“… Experimental observations were equally well reproduced by either of two kinetic schemes of SV priming and fusion: a single-pool model ( A ) or a recently proposed ( Lin et al, 2022 ) sequential two-step SV priming scheme ( B ). ( A1 ) Diagram of vesicle states for the single-pool model.…”

“…Since the loss of presynaptic Rac1 caused three principal changes in synaptic function: ( i ) increased synaptic strength ( Figure 2D1 ), ( ii ) increased steady-state release during 50 Hz stimulation ( Figure 2A2 ), and ( iii ) accelerated EPSC recovery following conditioning 500 Hz trains ( Figure 5 ), we next sought to corroborate our conclusions about underlying synaptic mechanisms by reproducing experimental data in numerical simulations. To do so, we used two distinct STP models: (1) a single-pool model with a Ca 2+- dependent SV pool replenishment similar to the release-site model of Weis et al, 1999 and (2) a recently established sequential two-step priming scheme ( Neher and Taschenberger, 2021 ; Lin et al, 2022 ).…”

“…Parameter values that differ between the models for Rac1 +/+ and Rac1 −/− synapses are listed in bold. For details, please refer to Lin et al, 2022 . For converting EPSC amplitudes measured in the presence of 1 mM kynurenic acid into quantal content, a quantal size of q =7.48 pA was assumed.…”

“…Subsequently, we simulated the experimental data using a two-step priming scheme, which postulates a sequential build-up of the SV fusion apparatus and distinguishes two distinct priming states: an immature loosely docked state (LS) and a mature tightly-docked (TS) state ( Neher and Brose, 2018 ; Neher and Taschenberger, 2021 ; Lin et al, 2022 ). The two-step priming scheme ( Figure 6B1 ) reproduces functional changes in Rac1 −/− synapses, including the accelerated EPSC recovery after pool depletion ( Figure 6B3 ), increased initial EPSC amplitudes, and elevated steady-state release during 50 Hz trains ( Figure 6B4 ).…”

“…Both experimental findings were corroborated in numerical simulation using a single-pool STP model ( Weis et al, 1999 ). In contrast, simulations based on a sequential two-step priming scheme which assumes two distinct states of docked/primed SVs, a loosely docked (LS), immature priming state which is not fusion competent, and a tightly docked (TS), mature priming state which is fusion competent ( Neher and Taschenberger, 2021 ; Lin et al, 2022 ), required only changes in SV priming kinetics but no change in P r or the number of release sites to reproduce experimental data. Simulations based on the sequential two-step SV priming and fusion scheme fully accounted for the increased synaptic strength in Rac1 −/− synapses by a larger abundance of tightly docked SVs.…”