Crosstalk between biochemical signaling and trafficking determines AMPAR dynamics in synaptic plasticity

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. Here, we have developed a set of models using compartmental ordinary differential equations to systematically investigate contributions of signaling and trafficking variations on AMPAR dynamics at the synaptic site. We find that the model properties including network architecture and parameters 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. Therefore, AMPAR dynamics can have unexpected dependencies when upstream signaling dynamics (such as CaMKII and PP1) are coupled with trafficking modalities.

Spatiotemporal modeling reveals geometric dependence of AMPAR dynamics on dendritic spine morphology

“…We saw that at these timescales, despite the localization of receptors and channels for calcium, all cytosolic species other than cytosolic AMPAR showed homogeneous spatial dynamics, Figure S1. Therefore, due to this homogeneity and the previous investigation of these signaling species [29, 43, 45, 46, 73], we will focus specifically on AMPAR spatiotemporal dynamics.…”

“…It has been proposed that CaMKII signaling can influence the trafficking of AMPAR from these pools into activated dendritic spines [22–24]. While these different aspects have been studied experimentally [15, 50, 54–57] and computationally [6, 7, 29, 48, 58, 59], a comprehensive spatiotemporal model that accounts for these different factors is missing in the literature. The roles of spatial localization and membrane-cytosol crosstalk of these biochemical interactions and the role of dendritic spine morphology in these processes are not well-known.…”

“…To investigate AMPAR spatiotemporal dynamics, we construct a simplified biochemical signaling network describing AMPAR dynamics, on the timescale of minutes, in hippocampal pyramidal CA1 neurons using deterministic reaction-diffusion equations, see Fig. 1a and [29]. Here we list the model assumptions, describe the key steps in the biochemical signaling cascade, provide the governing equations, and describe how the idealized and realistic spine morphologies were used for simulation purposes.…”

“…As a result there is no mass conservation for AMPAR in the system with influx. The model reactions are the same as those presented in [29] but translated to a spatial reaction-diffusion systems from a compartmental model. In some cases, the reactions occurring at the membrane were modeled using boundary conditions.…”

“…All the phosphatases are deactivated by active CaMKII. For our selected calcium influx and initial conditions of CaMKII and PP1, we expect a sustained high concentration of activated CaMKII following activation for this bistable model [29].…”