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

Abstract

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, though the mapping between spatio-temporal 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 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 which produce long lasting synaptic plasticity. Though the number of computer programs for computationally efficient simulation of large reaction-diffusion networks is increasing, parameter estimation and sensitivity analysis in these spatial model remains 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.

Levetiracetam Protects Against Cognitive Impairment of Subthreshold Convulsant Discharge Model Rats by Activating Protein Kinase C (PKC)-Growth-Associated Protein 43 (GAP-43)-Calmodulin-Dependent Protein Kinase (CaMK) Signal Transduction Pathway

“…Synaptic plasticity is the changes in synaptic strength (the structures or the functions) produced by the diverse-stimulation procedures in vitro and in vivo [43]. Whitlock et al [44] reported that synaptic plasticity is an important mechanism that underlies long-term memory storage.…”

A Computational Model for the AMPA Receptor Phosphorylation Master Switch Regulating Cerebellar Long-Term Depression

“…The model contains two compartments ( Fig 1 ). The sub-membrane compartment comprises the volume of cytosol directly below the plasma membrane to a distance of 120nm [ 80 ], and consists of three sub-compartments: postsynaptic density (PSD), endocytic zone (EZ) and extra-synaptic area. The sub-endosome compartment is assumed to occupy the same volume as the sub-membrane.…”

Increased molecular plasticity along the septotemporal axis of the hippocampus is associated with network functioning

“…Molecular plasticity represents a fundamental parameter in brain functioning that permits rapid adaptational responses of neural circuits to current need of the organism, thereby supporting complex brain functions like learning and memory by providing the building blocks for the formation of lasting changes at higher levels of neural organization (Ziv and Brenner 2018;Minatohara et al 2016;Diekelmann and Born 2010). Hence, mechanisms of molecular plasticity are essential in supporting maintained changes in synaptic transmission that underlie learning and memory (Shonesy et al 2014;Blackwell and Jedrzejewska-Szmek 2013;Elgersma and Silva 1999;Colbran 2015;Kotaleski and Blackwell 2010). Inversely, increased ability for plastic changes at synaptic, cellular and higher levels of brain organization is indicative of an increased ability for plastic changes at the molecular level (Koehl 2015).…”