Elsevier

Biosystems

Volume 122, August 2014, Pages 7-18
Biosystems

Review Article
Systems biology of synaptic plasticity: A review on N-methyl-d-aspartate receptor mediated biochemical pathways and related mathematical models

https://doi.org/10.1016/j.biosystems.2014.06.005Get rights and content

Abstract

Synaptic plasticity, an emergent property of synaptic networks, has shown strong correlation to one of the essential functions of the brain, memory formation. Through understanding synaptic plasticity, we hope to discover the modulators and mechanisms that trigger memory formation. In this paper, we first review the well understood modulators and mechanisms underlying N-methyl-d-aspartate receptor dependent synaptic plasticity, a major form of synaptic plasticity in hippocampus, and then comment on the key mathematical modelling approaches available in the literature to understand synaptic plasticity as the integration of the established functionalities of synaptic components.

Introduction

The mammalian brain consists of neurons and synapses that are interconnected into a complex neuronal network for information processing and memory storage. The network is robust in which its behavioural responses to environmental stimuli are rapid and precise, yet flexible to allow for desired durations of memory storage (Bear et al., 2007). The robustness as well as the flexibility of the neuronal network is hypothesised to be facilitated by a ‘plastic’ nature of synaptic transmission (see Bear et al., 2007 for the details of synaptic transmission) between two neurons (Bliss and Collingridge, 1993), named presynaptic and postsynaptic neurons with respect to their positions in the transmission. The ‘plastic’ nature denotes the ability to modulate synaptic strength, which reflects the degree of association between the environmental stimulus and the rate of the induced synaptic transmission. The modulation is dominated by a synaptic activity called synaptic plasticity (Kandel, 2009, Mayford et al., 2012).

The processes involved in synaptic plasticity have drawn wide interests from neuroscientists over the last two decades. Synaptic plasticity expresses multiple forms dependent on the expressing brain region and neuron type. The mechanisms, expressing sites and expressing targets are different among the different forms of synaptic plasticity (reviewed in Citri and Malenka, 2007). The most studied form is hippocampal N-methyl-d-aspartate receptor (NMDAR)-dependent synaptic plasticity because of the importance of hippocampus in the memory storage and retrieval, and the extensive experimental investigations during the last two decades in this area. For this particular form, synaptic plasticity is shown by the bidirectional modifications in the postsynaptic response following electrical stimulations (Bliss and Lømo, 1973, Bliss and Collingridge, 1993, Dudek and Bear, 1992). The postsynaptic response is represented by the magnitude of the postsynaptic receptor mediated current (EPSC) in vivo (Bliss and Lømo, 1973, Dudek and Bear, 1992). The major postsynaptic receptors in hippocampus are glutamatergic receptors, including NMDAR and A-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR). Thus, these receptors have critical roles in the emergence of synaptic plasticity.

With the abundant experimental data of synaptic components, modelling of synaptic plasticity enables the integration of the fragmented information of the synaptic components into a system level view to provide insights into the interactions and the roles of the main synaptic modulators contributing to synaptic plasticity (Kotaleski and Blackwell, 2010). The existing models related to synaptic plasticity help us to understand the structural and functional properties of synaptic proteins in the emergence of synaptic plasticity (Manninen et al., 2010). This review aims to illustrate the contribution of these modelling approaches to understand synaptic plasticity as the integration of the established functionalities of synaptic components that is a very important aspect of systems biology. We propose that synaptic plasticity and the associated phenomena such as memory formation need to be understood within this context of systems biology.

The individual molecular processes of synaptic plasticity are extensively reviewed in many papers. Hence, this review briefly illustrates the critical nature and specificities of these molecular processes in the emergence of synaptic plasticity and mainly focuses on describing the existing modelling approaches and insights provided by them to understand the emergent properties of the interacting network of synaptic plasticity. As a consequence, this review serves as an introduction to the field that integrates the necessary information of the modelling of synaptic plasticity. This review is separated into two sections. Section 1 describes the importance of synaptic plasticity and the extreme importance and specificity of the molecular processes involved in the emergence of synaptic plasticity. Section 2 presents a summary of the modelling approaches and the contributions of the existing models of synaptic plasticity. At the end of Section 2, we highlight research questions related to the modelling that need to be addressed in future.

Section snippets

NMDAR-dependent synaptic plasticity – from Ca2+ to alterations on AMPAR

Synaptic plasticity facilitates high level brain functions, such as memory formation, through its ability to modulate synaptic strength. Direct evidence shows that antagonists or gene mutations related to synaptic plasticity impair memory formation (Bourtchuladze et al., 1994, Chang et al., 1999, Davis et al., 1992, Giese et al., 1998, Morris, 1989, Silva et al., 1992a, Silva et al., 1992b). The exact relationship between synaptic plasticity and memory formation is far from completely

Mathematical models of the NMDAR-mediated pathways

The dynamic participation of the synaptic proteins in the sophisticated interacting networks gives rise to synaptic plasticity. In one facet of systems biology, we aim to understand the system level functions of synaptic proteins and their emergent properties through mathematical modelling of the interactions among synaptic proteins based on biophysics – chemical kinetics for example – and through the analysis of the emergent properties. Thus, mathematical modelling based on biologically

Future directions

There are many questions of synaptic functioning that may be critical for synaptic plasticity, which could be answered through modelling:

  • (1)

    How would the local dynamics of synaptic proteins impact synaptic plasticity? This problem deals with the co-localisation of synaptic proteins mediated by AKAPs and spatial movement of synaptic proteins among synaptic compartments. Hence, the models of this category need to be developed based on previously model findings and expanding with the spatial and

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