title: 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.
authors.affiliation: Department of Mechanical and Aerospace Engineering, University of California, San Diego, La Jolla, CA 92093; padmini.rangamani@eng.ucsd.edu goster@berkeley.edu.
authors.forename: Padmini
authors.initials: P
authors.lastname: Rangamani
authors.affiliation: Biophysics Graduate Program, University of California, Berkeley, CA 94720;
authors.forename: Michael G
authors.initials: MG
authors.lastname: Levy
authors.affiliation: Molecular Biology Consortium, Lawrence Berkeley National Laboratory, Berkeley, CA 94720;
authors.forename: Shahid
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720 padmini.rangamani@eng.ucsd.edu goster@berkeley.edu.
authors.forename: George
authors.initials: G
authors.lastname: Oster
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000737:chemistry / Q000378:metabolism; D049229:Dendritic Spines / Q000378:metabolism* / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008962:Models, Theoretical; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000737:chemistry / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000737:chemistry / Q000378:metabolism
chemical_list: D000199:Actins; D016194:Receptors, N-Methyl-D-Aspartate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D020764:cdc42 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein
keywords: CaMKII; actin; dendritic spine