Section: New Results

Mathematical modeling of neuronal excitability

Modeling cortical spreading depression induced by the hyperactivity of interneurons

Participants : Mathieu Desroches, Olivier Faugeras, Martin Krupa [LJAD, UCA, Inria MathNeuro] , Massimo Mantegazza [Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), Sophia Antipolis] .

Cortical spreading depression (CSD) is a wave of transient intense neuronal firing leading to a long lasting depolarizing block of neuronal activity. It is a proposed pathological mechanism of migraine with aura. Some forms of migraine are associated with a genetic mutation of the Na${}_{\mathrm{v}1.1}$ channel, resulting in its gain of function and implying hyperexcitability of interneurons. This leads to the counterintuitive hypothesis that intense firing of interneurons can cause CSD ignition. To test this hypothesis in silico, we developed a computational model of an E-I pair (a pyramidal cell and an interneuron), in which the coupling between the cells in not just synaptic, but takes into account also the effects of the accumulation of extracellular potassium caused by the activity of the neurons and of the synapses. In the context of this model, we show that the intense firing of the interneuron can lead to CSD. We have investigated the effect of various biophysical parameters on the transition to CSD, including the levels of glutamate or GABA, frequency of the interneuron firing and the efficacy of the KCC${}_2$ co-transporter. The key element for CSD ignition in our model was the frequency of interneuron firing and the related accumulation of extracellular potassium, which induced a depolarizing block of the pyramidal cell. This constitutes a new mechanism of CSD ignition.

This work has been published in Journal of Computational Neuroscience and is available as [25].

The extension of this work is the topic of the PhD of Louisiane Lemaire, who started in October 2018. A first part of Louisiane's PhD has been to improve and extend the model published in [25] in a number of ways: replace the GABAergic neuron model used in [25], namely the Wang-Buszáki model, by a more recent fast-spiking cortical interneuron model due to Golomb and collaborators; implement the effect of the HM1a toxin used by M. Mantegazza to mimic the genetic mutation of sodium channels responsible for the hyperactivity of the GABAergic neurons; take into account ionic concentration dynamics (relaxing the hypothesis of constant reversal potentials) for the GABAergic as well whereas in [25] this was done only for the Pyramidal neuron. This required a great deal of modelling and calibration and the simulation results are closer to the actual experiments by Mantegazza than in our previous study. A manuscript is in preparation.