Paradoxical signaling regulates structural plasticity in dendritic spines

Abstract

Transient spine enlargement (3-to 5-min timescale) is an important event associated with the structural plasticity of dendritic spines. Many of the molecular mechanisms associated with transient spine enlargement have been identified experimentally. Here, we use a systems biology approach to construct a mathematical model of biochemical signaling and actin-mediated transient spine expansion in response to calcium influx caused by NMDA receptor activation. We have identified that a key feature of this signaling network is the paradoxical signaling loop. Paradoxical components act bifunctionally in signaling networks, and their role is to control both the activation and the inhibition of a desired response function (protein activity or spine volume). Using ordinary differential equation (ODE)-based modeling, we show that the dynamics of different regulators of transient spine expansion, including calmodulin-dependent protein kinase II (CaMKII), RhoA, and Cdc42, and the spine volume can be described using paradoxical signaling loops. Our model is able to capture the experimentally observed dynamics of transient spine volume. Furthermore, we show that actin remodeling events provide a robustness to spine volume dynamics. We also generate experimentally testable predictions about the role of different components and parameters of the network on spine dynamics.CaMKII | dendritic spine | actin

Dendritic spine geometry and spine apparatus organization govern the spatiotemporal dynamics of calcium

“…In addition to the transient response of calcium, the cumulative calcium (total calcium) also carries information with respect to synaptic plasticity ( Bourne and Harris, 2008 ; Rangamani et al, 2016 ; Basak and Narayanan, 2018 ). Therefore, we calculated the integrated calcium over the entire spine volume (area under the curve [AUC]; Gorman and Sejnowski, 1988 ; Heinrich et al, 2002 ; Atay and Skotheim, 2017 ) over 300 ms. Calcium AUC at 300 ms ( Fig.…”

“…Dendritic spines, small protein- and actin-rich protrusions located on dendrites of neurons, have emerged as a critical hub for learning, memory, and synaptic plasticity in both short-term and long-term synaptic events ( Bourne and Harris, 2008 ; Rangamani et al, 2016 ). These subcompartments provide valuable surface area for cell–cell interaction at synapses, and compartmentalization of signaling proteins to control and process incoming signals from the presynaptic terminal ( Nishiyama and Yasuda, 2015 ; Yasuda, 2017 ).…”

“…Since calcium is the first incoming signal into the postsynaptic terminal, calcium temporal dynamics have been extensively studied experimentally and more recently computationally ( Denk et al, 1996 ; Augustine et al, 2003 ; Bloodgood and Sabatini, 2005 ; Bartol et al, 2015b ; Yasuda, 2017 ). In particular, calcium acts as a vital second messenger, triggering various signaling cascades that can lead to long-term potentiation, long-term depression, actin cytoskeleton rearrangements, and volume expansion, among other events ( Holmes, 1990 ; Bourne and Harris, 2008 ; Rangamani et al, 2016 ).…”

“…Dendritic spine activity has numerous timescales, with signaling pathways operating on the millisecond to the hour timescale following spine activation ( Yuste et al, 2000 ; Segal, 2005 ; Rangamani et al, 2016 ). Calcium dynamics are on the millisecond timescale, since calcium is the second messenger that floods the spine following the release of neurotransmitter from the presynaptic terminal.…”

“…In particular, fluorescent probes can sequester calcium, effectively acting as calcium buffers and lowering the perceived calcium concentrations. Therefore, computational studies have already provided some insight into the spatiotemporal dynamics of calcium in both dendritic spines ( Yuste et al, 2000 ; Segal, 2005 ; Rangamani et al, 2016 ) and whole neurons ( Loewenstein and Sompolinsky, 2003 ). In this study, we specifically focus on the effect of spine geometry on calcium signals in the postsynaptic spine.…”