Postsynaptic Stability and Variability Described by a Stochastic Model of Endosomal Trafficking

Neurons undergo dynamic processes of constitutive AMPA-type glutamate receptor (AMPAR) trafficking, such as the insertion and internalization of AMPARs by exocytosis and endocytosis, while stably maintaining synaptic efficacy. Studies using advanced imaging techniques have suggested that the frequency of these constitutive trafficking processes, as well as the number of AMPARs that are involved in a particular event highly fluctuate. In addition, mechanisms that trigger some forms of synaptic plasticity have been shown to include not only these processes but also additional fluctuating processes, such as the sorting of AMPARs to late endosomes (LEs). Thus, the regulation of postsynaptic AMPARs by the endosomal trafficking system appears to have superficially conflicting properties between the stability or organized control of plasticity and highly fluctuating or stochastic processes. However, it is not clear how the endosomal trafficking system reconciles and utilizes such conflicting properties. Although deterministic models have been effective to describe the stable maintenance of synaptic AMPAR numbers by constitutive recycling, as well as the involvement of endosomal trafficking in synaptic plasticity, they do not take stochasticity into account. In this study, we introduced the stochasticity into the model of each crucial machinery of the endosomal trafficking system. The specific questions we solved by our improved model are whether stability is accomplished even with a combination of fluctuating processes, and how overall variability occurs while controlling long-term synaptic depression (LTD). Our new stochastic model indeed demonstrated the stable regulation of postsynaptic AMPAR numbers at the basal state and during LTD maintenance, despite fast fluctuations in AMPAR numbers as well as high variability in the time course and amounts of LTD. In addition, our analysis suggested that the high variability arising from this stochasticity is beneficial for reproducing the relatively constant timing of LE sorting for LTD. We therefore propose that the coexistence of stability and stochasticity in the endosomal trafficking system is suitable for stable synaptic transmission and the reliable induction of synaptic plasticity, with variable properties that have been observed experimentally.