Presynaptic Terminals Dynamically Modulate Spontaneous Release Frequency During Early Synaptic Plasticity Through and Entropic Force Framework

Spontaneous synaptic transmission has been established as essential for the maintenance of synaptic weights during action potential-induced transmission. However, spontaneous transmission also changes during synaptic plasticity and has been shown to, in part, mediate changes in synaptic weights. Despite decades of research, a coherent framework for understanding the complex molecular processes that support presynaptic spontaneous transmission during maintenance and plasticity has remained elusive. We show here that presynapses modulate spontaneous transmission frequency during the early time-course of plasticity following entropic force theory. We use live primary hippocampal cultures as a model system and induce plasticity using an established Long-Term Potentiation (LTP) protocol. We then use a combination of electron microscopy, fluorescence microscopy, and computational modeling to show how spontaneous release frequency dynamically changes during early plasticity. We use our entropic force theory to show how the dynamically changing synaptic vesicle pool structure mediates spontaneous release changes. Lastly, we show how these changes are altered in the presence of P301L tau leading to degeneration. The results from this study provide new insights that not only help understand normal synaptic function but also aid in understanding neurodegeneration.