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WIREs Syst Biol Med
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Molecular mechanisms underlying neuronal synaptic plasticity: systems biology meets computational neuroscience in the wilds of synaptic plasticity

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Interactions among signaling pathways that are activated by transmembrane receptors produce complex networks and emergent dynamical behaviors that are implicated in synaptic plasticity. Temporal dynamics and spatial aspects are critical determinants of cell responses such as synaptic plasticity, although the mapping between spatiotemporal activity pattern and direction of synaptic plasticity is not completely understood. Computational modeling of neuronal signaling pathways has significantly contributed to understanding signaling pathways underlying synaptic plasticity. Spatial models of signaling pathways in hippocampal neurons have revealed mechanisms underlying the spatial distribution of extracellular signal‐related kinase (ERK) activation in hippocampal neurons. Other spatial models have demonstrated that the major role of anchoring proteins in striatal and hippocampal synaptic plasticity is to place molecules near their activators. Simulations of yet other models have revealed that the spatial distribution of synaptic plasticity may differ for potentiation versus depression. In general, the most significant advances have been made by interactive modeling and experiments; thus, an interdisciplinary approach should be applied to investigate critical issues in neuronal signaling pathways. These issues include identifying which transmembrane receptors are key for activating ERK in neurons, and the crucial targets of kinases that produce long‐lasting synaptic plasticity. Although the number of computer programs for computationally efficient simulation of large reaction–diffusion networks is increasing, parameter estimation and sensitivity analysis in these spatial models remain more difficult than in single compartment models. Advances in live cell imaging coupled with further software development will continue to accelerate the development of spatial models of synaptic plasticity. WIREs Syst Biol Med 2013, 5:717–731. doi: 10.1002/wsbm.1240 This article is categorized under: Biological Mechanisms > Cell Signaling Models of Systems Properties and Processes > Mechanistic Models

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Divergence, convergence, and positive and negative feedback loops. (a) Convergence from various transmembrane receptors to mitogen‐activated protein kinase (MAPK) phosphorylation. (b) Divergence from β‐adrenergic receptor (βAR) activation to multiple downstream effectors. The βAR is coupled to the Gαs type of G protein, but phosphorylation by PKA switches the association of the receptor from Gαs to the Gαi subtype of G protein. The cAMP produced by adenylyl cyclase can activate PKA, exchange factor activated by cAMP (EPAC), or cyclic nucleotide‐gated channels (CNG). (c) Positive feedback loop in which MAPK activates phospholipase A2 (PLA2) via phosphorylation, PLA2 produces arachidonic acid, which activates PKC, and PKC phosphorylation of both Raf and Ras activates MAPK. (d) Negative feedback loop involving PKA, phosphodiesterase type 4 (PDE4), and cAMP. A dashed line indicates that several intermediaries have been omitted.
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Spatial specificity in a striatal model of PKC and 2AG activation. (a) Calcium influx occurs through either N‐methyl‐d‐aspartate (NMDA) receptors or voltage‐gated calcium channels. The Gαq‐coupled metabotropic glutamate receptors are activated by glutamate binding. Gαq binding to phospholipase C leads to production of diacylglycerol (DAG). PKC is activated via calcium binding followed by DAG binding. 2AG is produced from DAG by DAG lipase. These pathways are implemented in a dendrite with 13 spines. The molecules associated with the membrane do not diffuse, but molecules shown in the cytoplasm diffuse freely. (b) No spatial specificity of 2AG, but (c) spatial specificity of PKC, is observed in response to theta‐burst stimulation (TBS). Input to the model consisted of a moderate calcium influx to the dendrite (representing neuron depolarization) and a larger calcium influx plus glutamate release to spine 1, representing synaptic activation of spine 1. This input was repeated in a theta‐burst pattern. (Reprinted with permission from Ref . Copyright 2013 Public Library of Science)
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Spatial aspect of signaling molecules in neurons. (a) The diffusional distance of cAMP produced by adenylyl cyclase (AC) is limited by degradation by various phosphodiesterase (PDE) isoforms. Because of this steep concentration gradient, PKA needs to be anchored near the AC for activation. (b) When anchoring of PKA is blocked, it resides outside of the domain of high cAMP concentration, and thus its activation is decreased. (c) When phosphodiesterases are blocked, cAMP diffuses further and the spatial gradient of cAMP is reduced, demonstrating the role of inactivation mechanisms for spatial gradients. A reduced spatial gradient lessens the need for PKA to be located near the site of cAMP production; thus, PKA can be activated even if not anchored near the AC.
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Biological Mechanisms > Cell Signaling
Models of Systems Properties and Processes > Mechanistic Models

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