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A Mechanistic Model of NMDA and AMPA Receptors-Mediated Synaptic Transmission in Individual Hippocampal CA3-CA1 Synapses: A Computational Multiscale Approach
Micheli, P.; Ribeiro, R.; Giorgetti, A. A Mechanistic Model of NMDA and AMPA Receptor-Mediated Synaptic Transmission in Individual Hippocampal CA3-CA1 Synapses: A Computational Multiscale Approach. Int. J. Mol. Sci.2021, 22, 1536.
Micheli, P.; Ribeiro, R.; Giorgetti, A. A Mechanistic Model of NMDA and AMPA Receptor-Mediated Synaptic Transmission in Individual Hippocampal CA3-CA1 Synapses: A Computational Multiscale Approach. Int. J. Mol. Sci. 2021, 22, 1536.
Micheli, P.; Ribeiro, R.; Giorgetti, A. A Mechanistic Model of NMDA and AMPA Receptor-Mediated Synaptic Transmission in Individual Hippocampal CA3-CA1 Synapses: A Computational Multiscale Approach. Int. J. Mol. Sci.2021, 22, 1536.
Micheli, P.; Ribeiro, R.; Giorgetti, A. A Mechanistic Model of NMDA and AMPA Receptor-Mediated Synaptic Transmission in Individual Hippocampal CA3-CA1 Synapses: A Computational Multiscale Approach. Int. J. Mol. Sci. 2021, 22, 1536.
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, that 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 pinpoint 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 few, key, molecular interactions typical of structural biology ones.
Keywords
CA3-CA1 synapses; NMDA; AMPA; systems biology; multiscale modeling; synaptic plasticity; long term potentiation; long term depression; hippocampus
Subject
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
