Paradoxical signaling regulates structural plasticity in dendritic spines

TL;DR

This paper develops a mathematical model of dendritic spine plasticity, highlighting the role of paradoxical signaling loops in controlling transient spine enlargement and providing insights into molecular mechanisms underlying synaptic plasticity.

Contribution

It introduces a systems biology model emphasizing paradoxical signaling in spine dynamics, integrating biochemical and actin remodeling processes.

Findings

Model captures experimentally observed spine volume dynamics

Paradoxical signaling loops regulate key molecular regulators

Actin remodeling enhances robustness of spine size changes

Abstract

Transient spine enlargement (3-5 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 due to 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 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 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.