Crosstalk between biochemical signalling network architecture and trafficking governs AMPAR dynamics in synaptic plasticity.

Synaptic plasticity involves 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; an increase in AMPAR corresponds to strengthening of synapses while a decrease in AMPAR density weakens synaptic connections. The dynamics of AMPAR are thought to be regulated by upstream signalling, primarily the calcium-CaMKII pathway, trafficking to and from the synapse, and influx from extrasynaptic sources. Previous work in the field of deterministic modelling of CaMKII dynamics has assumed bistable kinetics, while experiments and rule-based modelling have revealed that CaMKII dynamics can be either monostable or ultrasensitive. This raises the following 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 signalling and trafficking variations, along with their coupled effects, on AMPAR dynamics at the synaptic site. We find that the properties of the model 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 (1) the choice of signalling model (bistable CaMKII or monostable CaMKII dynamics), (2) trafficking versus influx contributions and (3) frequency of stimulus. KEY POINTS: The density of AMPA receptors (AMPARs) at the postsynaptic density of the synapse provides a readout of synaptic plasticity, which involves crosstalk between complex biochemical signalling 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 aspects of biochemical signalling and trafficking. Specifically, assumptions regarding CaMKII dynamics and its stability features can alter AMPAR density at the synapse. Our model also predicts that the kinetics of trafficking versus influx of AMPAR from the extrasynaptic space can further impact AMPAR density. Thus, the contributions of both signalling and trafficking should be considered in computational models.

Electrical signals in the ER are cell type and stimulus specific with extreme spatial compartmentalization in neurons.

The endoplasmic reticulum (ER) is a tortuous organelle that spans throughout a cell with a continuous membrane containing ion channels, pumps, and transporters. It is unclear if stimuli that gate ER ion channels trigger substantial membrane potential fluctuations and if those fluctuations spread beyond their site of origin. Here, we visualize ER membrane potential dynamics in HEK cells and cultured rat hippocampal neurons by targeting a genetically encoded voltage indicator specifically to the ER membrane. We report the existence of clear cell-type- and stimulus-specific ER membrane potential fluctuations. In neurons, direct stimulation of ER ryanodine receptors generates depolarizations that scale linearly with stimulus strength and reach tens of millivolts. However, ER potentials do not spread beyond the site of receptor activation, exhibiting steep attenuation that is exacerbated by intracellular large conductance K+ channels. Thus, segments of ER can generate large depolarizations that are actively restricted from impacting nearby, contiguous membrane.

Spatiotemporal modelling reveals geometric dependence of AMPAR dynamics on dendritic spine morphology.

The modification of neural circuits depends on the strengthening and weakening of synaptic connections. Synaptic strength is often correlated to the density of the ionotropic, glutamatergic receptors, AMPARs, (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) at the postsynaptic density (PSD). While AMPAR density is known to change based on complex biological signalling cascades, the effect of geometric factors such as dendritic spine shape, size and curvature remain poorly understood. In this work, we developed a deterministic, spatiotemporal model to study the dynamics of AMPARs during long-term potentiation (LTP). This model includes a minimal set of biochemical events that represent the upstream signalling events, trafficking of AMPARs to and from the PSD, lateral diffusion in the plane of the spine membrane, and the presence of an extrasynaptic AMPAR pool. Using idealized and realistic spine geometries, we show that the dynamics and increase of bound AMPARs at the PSD depends on a combination of endo- and exocytosis, membrane diffusion, the availability of free AMPARs and intracellular signalling interactions. We also found non-monotonic relationships between spine volume and the change in AMPARs at the PSD, suggesting that spines restrict changes in AMPARs to optimize resources and prevent runaway potentiation. KEY POINTS: Synaptic plasticity involves dynamic biochemical and physical remodelling of small protrusions called dendritic spines along the dendrites of neurons. Proper synaptic functionality within these spines requires changes in receptor number at the synapse, which has implications for downstream neural functions, such as learning and memory formation. In addition to being signalling subcompartments, spines also have unique morphological features that can play a role in regulating receptor dynamics on the synaptic surface. We have developed a spatiotemporal model that couples biochemical signalling and receptor trafficking modalities in idealized and realistic spine geometries to investigate the role of biochemical and biophysical factors in synaptic plasticity. Using this model, we highlight the importance of spine size and shape in regulating bound AMPA receptor dynamics that govern synaptic plasticity, and predict how spine shape might act to reset synaptic plasticity as a built-in resource optimization and regulation tool.

Dendritic spine morphology regulates calcium-dependent synaptic weight change.

Dendritic spines act as biochemical computational units and must adapt their responses according to their activation history. Calcium influx acts as the first signaling step during postsynaptic activation and is a determinant of synaptic weight change. Dendritic spines also come in a variety of sizes and shapes. To probe the relationship between calcium dynamics and spine morphology, we used a stochastic reaction-diffusion model of calcium dynamics in idealized and realistic geometries. We show that despite the stochastic nature of the various calcium channels, receptors, and pumps, spine size and shape can modulate calcium dynamics and subsequently synaptic weight updates in a deterministic manner. Through a series of exhaustive simulations and analyses, we found that the calcium dynamics and synaptic weight change depend on the volume-to-surface area of the spine. The relationships between calcium dynamics and spine morphology identified in idealized geometries also hold in realistic geometries, suggesting that there are geometrically determined deterministic relationships that may modulate synaptic weight change.

Mechanical Principles Governing the Shapes of Dendritic Spines.

Dendritic spines are small, bulbous protrusions along the dendrites of neurons and are sites of excitatory postsynaptic activity. The morphology of spines has been implicated in their function in synaptic plasticity and their shapes have been well-characterized, but the potential mechanics underlying their shape development and maintenance have not yet been fully understood. In this work, we explore the mechanical principles that could underlie specific shapes using a minimal biophysical model of membrane-actin interactions. Using this model, we first identify the possible force regimes that give rise to the classic spine shapes-stubby, filopodia, thin, and mushroom-shaped spines. We also use this model to investigate how the spine neck might be stabilized using periodic rings of actin or associated proteins. Finally, we use this model to predict that the cooperation between force generation and ring structures can regulate the energy landscape of spine shapes across a wide range of tensions. Thus, our study provides insights into how mechanical aspects of actin-mediated force generation and tension can play critical roles in spine shape maintenance.