Dendritic spine morphology regulates calcium-dependent synaptic weight change

Abstract

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.

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

“…We found that there is a resetting of the bound‐AMPAR density (or percentage change) between the two spine shapes, despite the increase in spine volume (and volume‐to‐SA ratio) between the thin and mushroom spines. This trend matches the pattern found for synaptic weight updates based on Ca 2+ influx into dendritic spines of different sizes and geometries Bell et al, 2022. Therefore, we predict that thin spines are able to increase the density of bound‐AMPAR density more rapidly for increases in their volume; while in comparison, mushroom spines have a slower increase in density as volume increases.…”

“…We saw that at these timescales, despite the localization of receptors and channels for calcium, all cytosolic species other than cytosolic AMPARs showed homogeneous spatial dynamics. Therefore, due to this homogeneity and the previous investigation of these signalling species (Bell & Rangamani, 2021; Bell et al., 2019, 2022; Cugno et al., 2019; Ordyan et al., 2020), we will focus specifically on AMPAR spatiotemporal dynamics.…”

“…However, more recent analyses have brought these exact relationships into question, suggesting a more complex regulation of AMPARs at the PSD (Borczyk et al., 2019). Furthermore, the shape of dendritic spines is known to influence signalling (Bartol et al., 2015; Bell et al., 2019, 2022; Cugno et al., 2019), but it is unknown how spine geometry couples with trafficking mechanisms and signalling to regulate AMPAR dynamics at the PSD. Role of trafficking Trafficking modalities of interest include mechanisms that can alter the number of AMPARs at the PSD and generally in different regions of the dendritic spine. These modalities include endocytosis/exocytosis, trafficking into the dendritic spine from extrasynaptic pools on the dendrite, and diffusion within subregions of the spine, and can be dependent on upstream biochemical interactions.…”

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

“… In response to a glutamate release event coupled with a voltage stimulus [primarily, an EPSP and a backpropagating action potential (BPAP)], NMDA receptors (NMDARs) and voltage sensitive calcium channels (VSCCs) open on the spine membrane, resulting in an influx of Ca 2+ into the spine. Calcium influx into the spine is the first step in numerous different signalling pathways important for synaptic function and from a modelling perspective is one of the most studied events in spines (Bartol et al., 2015; Basnayake et al., 2019; Bell et al., 2019, 2022; Cugno et al., 2019; Leung et al., 2021; Li et al., 2012; Mahajan & Nadkarni, 2019; Ohadi & Rangamani, 2019; Ohadi et al., 2019). This voltage depolarization and subsequent calcium influx occurs over the millisecond time scale. Cytosolic Ca 2+ rapidly binds a variety of different species over the millisecond to second time scale, notably calmodulin (CaM) (Keller et al., 2008; Li et al., 2012; Stefan et al., 2008), which in turn triggers various kinases and phosphatases including calcium/calmodulin‐dependent protein kinase II (CaMKII) and protein phosphatase 1 (PP1) (Colbran, 2004; Mäki‐Marttunen et al., 2020; Pi & Lisman, 2008).…”

“…This voltage depolarization and subsequent calcium influx occurs over the millisecond time scale. Cytosolic Ca 2+ rapidly binds a variety of different species over the millisecond to second time scale, notably calmodulin (CaM) (Keller et al., 2008; Li et al., 2012; Stefan et al., 2008), which in turn triggers various kinases and phosphatases including calcium/calmodulin‐dependent protein kinase II (CaMKII) and protein phosphatase 1 (PP1) (Colbran, 2004; Mäki‐Marttunen et al., 2020; Pi & Lisman, 2008). Free cytosolic Ca 2+ is also bound to various calcium buffers both in the cytoplasm and located on the membrane (Bell et al., 2019, 2022; Schmidt, 2012). CaM additionally binds to scaffolding proteins such as neurogranin (Ng), which impacts the available CaM for CaMKII activation (Ordyan et al., 2020; Prichard et al., 1999).…”