EONS

 

www.synapticmodeling.com

EONS (Elementary objects of the Nervous System) is the perfect modeling platform to study the dynamic interactions between synaptic elements in a friendly manner. There are no complicated equations to write: all the elementary models are predefined using state of the art models.

EONS consists of a graphical modeling platform containing the major elements that comprise a glutamatergic synapse (both pre- and post-synaptically). These elements parameters as well as the underlying synaptic geometry can be modified.

EONS is a parametric model of a generic glutamatergic synapse that takes into account pre-synaptic mechanisms, such as calcium buffering and diffusion, neurotransmitter release, diffusion and uptake in the cleft, and postsynaptic elements, such as ionotropic AMPA and NMDA receptors, their distribution and synaptic geometry, as well as metabotropic glutamate receptors.

 

Research

EONS is a parametric model of a generic glutamatergic synapse [1] that takes into account pre-synaptic mechanisms, such as calcium buffering and diffusion, neurotransmitter release, diffusion and uptake in the cleft (including glial glutamate uptake), and postsynaptic elements, such as ionotropic AMPA and NMDA receptors [2], their distribution and synaptic geometry, as well as metabotropic glutamate receptors [3]. EONS is a unique platform that allows to study the dynamic non-linear interactions that take place between the various synaptic elements to shape synaptic transmission and plasticity.

EONS is being integrated with the NEURON simulator in a multiscale framework to extend the simulated spatial scales from biomolecular level to network level.

Molecular level to network hippocampus

Fig.1: Schematic representation of the different levels of complexity addressed in the multi-scale modeling platform. Molecular mechanisms, such as the AMPA receptors, are represented by a 16-state kinetic model (ref: TBME, 2011). At the subcellular level, these mechanisms are geometrically coupled, based on their location in the cell (presynaptic, extracellular, postsynaptic, or along the dendritic tree); the resulting changes in postsynaptic currents are then injected in a CA1 pyramidal cell neuron, which can be studied in isolation, or within a network.

 

Below is an example of the use of EONS in which we study the effects of an AMPA receptor modulator on AMPA receptor current (biomolecular level), synaptic transmission (synaptic level) and subsequent neuronal excitability (neuron level). The modulator changes the AMPA receptor current in a dose-dependent manner (Fig. 2).

CX614 study AMPA unitary response

 

Fig. 2: Effects of different concentrations of the positive AMPA receptor modulator, CX614, on the current going through AMPA receptor channels in the synaptic modeling platform resulting from a 1ms long single pulse of 1mM glutamate.


These changes affect overall synaptic responses through a change in AMPA-mediated current. The synapses are then placed on the dendritic tree of a CA1 pyramidal cell and we study the effects of changes in modulator concentration on the cell's response to a stimulation pattern thereby allowing us to study how excitability is affected at the neuronal level (Fig. 3).

CX614 study spike timing compilation v02

 

Fig. 3: Effects of different concentrations of the positive AMPA receptor modulator, CX614, on postsynaptic somatic potential of a CA1 hippocampal neuron in response to a random inter-pulse interval stimulation at a mean frequency of 4 Hz. Responses are shown for a 300 millisecond window. In the presence of CX614, note the increase in frequency of action potentials (*). Bottom: Timing of the postsynaptic spikes at various concentrations of CX614; presynaptic action potential (input) is compared to the timing of the postsynaptic spikes. Note that spikes occur earlier with increasing CX614 concentration.

 

The framework developed allows for incorporation of a high level of details at the molecular level into larger scale simulations. It is currently being extended to allow for simulations spanning (i) higher temporal scales and (ii) higher spatial scales (up to circuit-level simulations). Details of this example study are available in [4].

In parallel to this work, we are developing a non-parametric version of EONS that captures the complex non-linear dynamics of our synaptic platform in a computationally extremely compact envelop. Preliminary benchmarks indicate over a thousand-fold increase in computational speed, with virtually identical results.

 

Publications

[1] J.-M. C. Bouteiller, M. Baudry, S. L. Allam, R. J. Greget, S. Bischoff and T. W. Berger, "Modeling Glutamatergic Synapses: Insights into Mechanisms Regulating Synaptic Efficacy," Journal of Integrative Neuroscience, vol. 7(2), pp.185-97, 2008.

[2] Ambert, N., Greget, R., Haeberlé, O., Bischoff, S., Berger, T. W., Bouteiller, J-M. C., Baudry, M., Computational Studies of NMDA Receptors: Differential Effects of Neuronal Activity on Efficacy of Competitive and Noncompetitive Antagonists. Open Access Bioinformatics, August 2010, Volume 2010:2, pp. 113 – 125.

[3] Greget R., Pernot F., Bouteiller J-M. C., Ghaderi V., Allam S. L., Keller A. F., Ambert N., Sarmis M., Haeberle O., Faupel M., Bischoff S., Berger T. W., Baudry M., Simulation of Postsynaptic Glutamate Receptors Reveals Critical Features of Glutamatergic Transmission", PLoS ONE 6(12): e28380. doi:10.1371/journal.pone.0028380.

[4] Bouteiller J-M. C., Allam S. L., Hu E. Y., Greget R., Ambert N., Keller A. F., Bischoff S., Baudry M., Berger T. W., Integrated Multi-Scale Modeling of the Nervous System: Predicting Changes in Hippocampal Network Activity by a Positive AMPA Receptor Modulator, Transactions on Biomedical Engineering, October 2011, Volume 58:10, pp. 3008-3011.

 

EONS Team:

Jean-Marie C. Bouteiller, PhD
Sushmita Allam, PhD
Eric Hu
Mike Huang
Viviane Ghaderi