From Atoms to Neuronal Spikes: A Multi-Scale Simulation Framework

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract Understanding how molecular events in ion channels impact neuronal excitability, as derived from the calculation of the time course of the membrane potentials, can help elucidate the mechanisms of neurological disease-linked mutations and support neuroactive drug design. Here, we propose a multi-scale simulation approach which couples molecular simulations with neuronal simulations to predict the variations in membrane potential and neural spikes. We illustrate this through two examples. First, molecular dynamics simulations predict changes in current and conductance through the AMPAR neuroreceptor when transitioning from the wild-type protein to certain disease-associated variants. The results of these simulations inform morphologically detailed models of cortical pyramidal neurons, which are simulated using the Arbor framework to determine neural spike activity. Based on these multiscale simulations, we suggest that disease associated AMPAR variants may significantly impact neuronal excitability. In the second example, the Arbor model is coupled with coarse-grained Monte Carlo gating simulations of voltage-gated (K + and Na + ) channels. The pre-dicted current from these ion channels altered the membrane potential and, in turn, the excitation state of the neuron was updated in Arbor. The resulting membrane potential was then fed back into the Monte Carlo simulations of the voltage-gated ion channels, resulting in a bidirectional coupling of current and membrane potential. This allowed the transitions of the states of the ion channels to influence the membrane potentials and vice versa. Our simulations also included the crucial — so far unexplored — effects of the composition of the lipid membrane embedding the ion channels on the membrane potential and revealed a significant impact of temperature on the neuronal excitability. Our combined approaches predicted membrane potentials consistent with electrophysiological recordings and established a multi-scale framework linking the atomistic perturbations to neuronal excitability.

Authors 6

1. Vincenzo Carnevale

   Temple University

   Affiliation as printed

   Institute for Computational Molecular Science, Temple University, Philadelphia, PA 19122, USA

   Institute for Genomics and Evolutionary Medicine, Temple University, Philadelphia, PA 19122, USA

   Temple University

2. Thorsten Hater

   Forschungszentrum Jülich · Jülich Supercomputing Centre

   Affiliation as printed

   Simulation and Data Lab Neuroscience, Forschungszentrum Jülich GmbH, Jülich Supercomputing Centre (JSC), 52428 Jülich, Germany

   Forschungszentrum Julich GmbH

3. Nauman Sultan

   National Institutes of Health · Johns Hopkins University · National Heart, Lung, and Blood Institute

   Affiliation as printed

   Department of Physics & Astronomy, Johns Hopkins University, Baltimore, MD 21218, USA

   National Heart, Lung, and Blood Institute; National Institutes of Health, USA

   Johns Hopkins University

4. Giulia Rossetti Aachen Department of Neurology

   Forschungszentrum Jülich · Universitätsklinikum Aachen · Jülich Supercomputing Centre

   Affiliation as printed

   Computational Biomedicine, Institute for Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, 52428 Jülich, Germany

   Department of Neurology, University Hospital Aachen, Pauwelsstraße 30, 52074 Aachen, Germany

   Simulation and Data Lab Biology, Jülich Supercomputing Centre (JSC), 52428 Jülich, Germany

   Forschungszentrum Julich

5. Sandra Diaz-Pier

   Forschungszentrum Jülich · Jülich Supercomputing Centre

   Affiliation as printed

   Simulation and Data Lab Neuroscience, Forschungszentrum Jülich GmbH, Jülich Supercomputing Centre (JSC), 52428 Jülich, Germany

   Forschungszentrum Julich GmbH

6. Paolo Carloni corresponding

   Forschungszentrum Jülich

   Affiliation as printed

   Computational Biomedicine, Institute for Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, 52428 Jülich, Germany

   Forschungszentrum Julich GmbH