Crosstalk between biochemical signaling network architecture & trafficking governs AMPAR dynamics in synaptic plasticity.

The density of AMPA receptors at the postsynaptic density of synapse is a readout of synaptic plasticity, which involves crosstalk between complex biochemical signaling networks including CaMKII dynamics and trafficking pathways including exocytosis and endocytosis Here we build a model that integrates CaMKII dynamics and AMPAR trafficking to explore this crosstalk. We compare different models of CaMKII that result in monostable or bistable kinetics and their impact on AMPAR dynamics. Our results show that AMPAR density depends on the coupling between biochemical signaling and trafficking aspects. Specifically assumptions about CaMKII dynamics and its stability features can alter AMPAR density at the synapse. Our model also predicts that kinetics of trafficking versus influx of AMPAR from the extrasynaptic space can further impact AMPAR density. Thus, both signaling and trafficking contributions should be considered in computational models. ABSTRACT: Synaptic plasticity involves the modification of both biochemical and structural components of neurons. Many studies have revealed that the change in the number density of the glutamatergic receptor AMPAR at the synapse is proportional to synaptic weight update; increase in AMPAR corresponds to strengthening of synapses while decrease in AMPAR density weakens synaptic connections. The dynamics of AMPAR are thought to be regulated by upstream signaling, primarily the calcium-CaMKII pathway, trafficking to and from the synapse, and influx from extrasynaptic sources. Previous work in the field of deterministic modeling CaMKII dynamics has assumed bistable kinetics, while experiments and rule-based modeling have revealed that CaMKII dynamics can either be monostable or ultrasensitive. This raises the question: how does the choice of model assumptions involving CaMKII dynamics influence AMPAR dynamics at the synapse? To answer this question, we have developed a set of models using compartmental ordinary differential equations to systematically investigate contributions of different signaling and trafficking variations, along with their coupled effects, on AMPAR dynamics at the synaptic site. We find that the model properties including network architecture describing different stability features of CaMKII and parameters that capture the endocytosis and exocytosis of AMPAR significantly affect the integration of fast upstream species by slower downstream species. Furthermore, we predict that the model outcome, as determined by bound AMPAR at the synaptic site, depends on (a) the choice of signaling model (bistable CaMKII or monostable CaMKII dynamics), (b) trafficking versus influx contributions, and (c) frequency of stimulus. Abstract figure legend Computational modeling demonstrates how biochemical signaling architecture coupled to AMPAR trafficking influences the synaptic response of AMPAR at the postsynaptic density. Dr. Miriam Bell received her BS in Physics from Harvey Mudd College in 2016 before receiving her PhD in Mechanical Engineering under the supervision of Professor Padmini Rangamani in 2022. Her work focuses on the interplay between biochemical signaling and cellular geometry in dendritic spines. She is a strong believer in the benefits of combining experimental and computational approaches to investigate biological phenomena. This article is protected by copyright. All rights reserved.