A Mechanistic Model of NMDA and AMPA Receptor-Mediated Synaptic Transmission in Individual Hippocampal CA3-CA1 Synapses: A Computational Multiscale Approach.

Pietro Micheli,Rui Ribeiro,Alejandro Giorgetti

doi:10.3390/ijms22041536

Abstract

Inside hippocampal circuits, neuroplasticity events that individual cells may undergo during synaptic transmissions occur in the form of Long-Term Potentiation (LTP) and Long-Term Depression (LTD). The high density of NMDA receptors expressed on the surface of the dendritic CA1 spines confers to hippocampal CA3-CA1 synapses the ability to easily undergo NMDA-mediated LTP and LTD, which is essential for some forms of explicit learning in mammals. Providing a comprehensive kinetic model that can be used for running computer simulations of the synaptic transmission process is currently a major challenge. Here, we propose a compartmentalized kinetic model for CA3-CA1 synaptic transmission. Our major goal was to tune our model in order to predict the functional impact caused by disease associated variants of NMDA receptors related to severe cognitive impairment. Indeed, for variants Glu413Gly and Cys461Phe, our model predicts negative shifts in the glutamate affinity and changes in the kinetic behavior, consistent with experimental data. These results point to the predictive power of this multiscale viewpoint, which aims to integrate the quantitative kinetic description of large interaction networks typical of system biology approaches with a focus on the quality of a few, key, molecular interactions typical of structural biology ones.

Highlights

Ionotropic glutamatergic receptors are a class of membrane receptors divided into three main subtypes, classified according to their activation to the selective agonists: NMDA (N-Methyl-D-aspartic acid), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), and Kainato
The second part contains the simulation of the model under different parameter configurations. This allows us to infer some qualitative features of the system, with a particular focus on the timing between pre and post-synaptic stimuli, and to assess shifts in the global system behavior given by the introduction of rare variants in the NMDA receptors associated with diseases
Because we had observed that the presence of a back-propagating action potentials (bAPs) during stimulation significantly increases the NMDA receptor mediated excitatory post-synaptic currents (EPSCs), we analyzed how variations in temporal coordination level between pre- and post-synaptic stimuli impacts the amplitude of the elicited Ca2+ influx

Summary

Introduction

Ionotropic glutamatergic receptors are a class of membrane receptors divided into three main subtypes, classified according to their activation to the selective agonists: NMDA (N-Methyl-D-aspartic acid), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), and Kainato They play a key role in the process of synaptic transmission, which takes place in excitatory glutamatergic synapses, and dysregulations in their normal activities have been widely linked to numerous neurological disorders and synaptopathies [1,2,3,4,5]. NMDA and AMPA receptors have been identified as crucial in the molecular mechanism underlying the process of synaptic plasticity, a process that leads to the modulation in the strength of the neuronal response to stimulation, linked to learning and memory [6,7,8] Complex cognitive functions such as learning and multiple forms of memory are carried out by the hippocampal formation, which can dynamically sample, encode, store, and retrieve information coming from the sensory experience [9,10,11]. The high density of NMDA receptors expressed on the surface of the dendritic CA1 spines confers to this synapse the ability to undergo NMDA receptor-mediated LTP and LTD, which has been substantially evidenced to be essential for some forms of explicit learning in mammals [12,13]

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Conclusion