New insights into short-term synaptic facilitation at the frog neuromuscular junction

Abstract

Short-term synaptic facilitation occurs during high-frequency stimulation, is known to be dependent on presynaptic calcium ions, and persists for tens of milliseconds after a presynaptic action potential. We have used the frog neuromuscular junction as a model synapse for both experimental and computer simulation studies aimed at testing various mechanistic hypotheses proposed to underlie short-term synaptic facilitation. Building off our recently reported excess-calcium-binding-site model of synaptic vesicle release at the frog neuromuscular junction (Dittrich M, Pattillo JM, King JD, Cho S, Stiles JR, Meriney SD. Biophys J 104: 2751–2763, 2013), we have investigated several mechanisms of short-term facilitation at the frog neuromuscular junction. Our studies place constraints on previously proposed facilitation mechanisms and conclude that the presence of a second class of calcium sensor proteins distinct from synaptotagmin can explain known properties of facilitation observed at the frog neuromuscular junction. We were further able to identify a novel facilitation mechanism, which relied on the persistent binding of calcium-bound synaptotagmin molecules to lipids of the presynaptic membrane. In a real physiological context, both mechanisms identified in our study (and perhaps others) may act simultaneously to cause the experimentally observed facilitation. In summary, using a combination of computer simulations and physiological recordings, we have developed a stochastic computer model of synaptic transmission at the frog neuromuscular junction, which sheds light on the facilitation mechanisms in this model synapse.

Rapid regulation of vesicle priming explains synaptic facilitation despite heterogeneous vesicle:Ca2+ channel distances

“…This is consistent with a previously described 212 single Ca 2+ -triggered release event (Lou et al, 2005). As this model lacks a specialized mechanism 285 to induce facilitation, residual Ca 2+ binding to the Ca 2+ -sensor is the only facilitation method which 286 appears to be insufficient (Jackman and Regehr, 2017;Ma et al, 2015;Matveev et al, 2002). This 287 result differs from our previous study using this model where we had placed all SVs at the same 288 distance to Ca 2+ channels which reliably produced STF (Bohme et al, 2016).…”

“…Similarly, stochastic modelling of NT release at the frog NMJ also showed a beneficial effect of a 321 second fusion sensor for STF (Ma et al, 2015). We therefore explored whether a dual fusion sensor 322 model could account for synaptic facilitation from realistic release site topologies.…”

A Gradient in Synaptic Strength and Plasticity among Motoneurons Provides a Peripheral Mechanism for Locomotor Control

“…Short-term synaptic plasticity including both depression and potentiation has been reported at the neuromuscular junction (NMJ) of different species [16, 23–25]. We next examined whether there is a systematic difference between activity dependent synaptic plasticity at NMJs of motoneurons with different Rins.…”

Myasthenia Gravis: From the Viewpoint of Pathogenicity Focusing on Acetylcholine Receptor Clustering, Trans-Synaptic Homeostasis and Synaptic Stability

“…Of note, the M1 mAChR is physiologically associated with the non-voltage-gated Ca 2+dominant influx channel (Transient receptor potential canonical; Kim and Saffen, 2005), the antibodies against which were positive in 7 (28%) of our 25 MG patients (Takamori, 2008b). An alternative theory postulated is that the impaired compensatory mechanism could be referred to the reduction in homeostatic small reserve pool of synaptic vesicles that depends on presynaptic adenosine A2A receptor operating Ca 2+ influx via L-type VGCC (Oliverira et al, 2004;Ma et al, 2015;Wang et al, 2016). In a long-tetanic load in muscle, the complex compensatory mechanisms including the presynaptic autoreceptors and Ca 2+ influx channel(s) may underlie to compensatory postsynaptic dysfunction.…”