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Modeling cortical spreading depression induced by the hyperactivity of interneurons

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Abstract

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 Nav1.1 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 KCC2 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.

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Funding

European Union projects DESIRE (grant n. EFP7-602531 to MM) and Investissements d’Avenir-Laboratory of Excellence “Ion Channels Science and Therapeutics” (grant LabEx ICST ANR-11-LABX-0015-01 to MM). ERC Advanced Grant Nervi 227747 (to OF).

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Authors and Affiliations

  1. MathNeuro Team, Inria Sophia Antipolis Méditerranée, 06902, Sophia Antipolis Cedex, France

    Mathieu Desroches, Olivier Faugeras & Martin Krupa

  2. Université Côte d’Azur, 06108, Nice Cedex 2, France

    Mathieu Desroches, Olivier Faugeras, Martin Krupa & Massimo Mantegazza

  3. JAD Laboratory, Université de Nice Sophia Antipolis, 06108, Nice Cedex 2, France

    Martin Krupa

  4. CNRS UMR7275, Institute of Molecular and Cellular Pharmacology (IPMC), LabEx ICST, 06560, Valbonne-Sophia Antipolis, France

    Massimo Mantegazza

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  1. Mathieu Desroches
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  2. Olivier Faugeras
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Correspondence to Martin Krupa.

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Desroches, M., Faugeras, O., Krupa, M. et al. Modeling cortical spreading depression induced by the hyperactivity of interneurons. J Comput Neurosci 47, 125–140 (2019). https://doi.org/10.1007/s10827-019-00730-8

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  • DOI: https://doi.org/10.1007/s10827-019-00730-8

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