Idealized multiple-timescale model of cortical spreading depolarization initiation and pre-epileptic hyperexcitability caused by NaV1.1/SCN1A mutations - Laboratoire Jean-Alexandre Dieudonné Accéder directement au contenu
Article Dans Une Revue Journal of Mathematical Biology Année : 2023

Idealized multiple-timescale model of cortical spreading depolarization initiation and pre-epileptic hyperexcitability caused by NaV1.1/SCN1A mutations

Résumé

NaV1.1 (SCN1A) is a voltage-gated sodium channel mainly expressed in GABAergic neurons. Loss of function mutations of NaV1.1 lead to epileptic disorders, while gain of function mutations cause a migraine in which cortical spreading depolarizations (CSDs) are involved. It is still debated how these opposite effects initiate two different manifestations of neuronal hyperactivity: epileptic seizures and CSD. To investigate this question, we previously built a conductance-based model of two neurons (GABAergic and pyramidal), with dynamic ion concentrations (Lemaire et al. in PLOS Comput. Biol. 17(7):e1009239, 2021). When implementing either NaV1.1 migraine or epileptogenic mutations, ion concentration modifications acted as slow processes driving the system to the corresponding pathological firing regime. However, the large dimensionality of the model complicated the exploitation of its implicit multi-timescale structure. Here, we substantially simplify our biophysical model to a minimal version more suitable for bifurcation analysis. The explicit timescale separation allows us to apply slow-fast theory, where slow variables are treated as parameters in the fast singular limit. In this setting, we reproduce both pathological transitions as dynamic bifurcations in the full system. In the epilepsy condition, we shift the spike-terminating bifurcation to lower inputs for the GABAergic neuron, to model an increased susceptibility to depolarization block. The resulting failure of synaptic inhibition triggers hyperactivity of the pyramidal neuron. In the migraine scenario, spiking-induced release of potassium leads to the abrupt increase of the extracellular potassium concentration. This causes a dynamic spike-terminating bifurcation of both neurons, which we interpret as CSD initiation.
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Dates et versions

hal-04108905 , version 1 (29-05-2023)

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Louisiane Lemaire, Mathieu Desroches, Martin Krupa, Massimo Mantegazza. Idealized multiple-timescale model of cortical spreading depolarization initiation and pre-epileptic hyperexcitability caused by NaV1.1/SCN1A mutations. Journal of Mathematical Biology, 2023, 86 (6), pp.92. ⟨10.1007/s00285-023-01917-5⟩. ⟨hal-04108905⟩
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