Modeling NaV1.1/SCN1A sodium channel mutations in a microcircuit with realistic ion concentration dynamics suggests differential GABAergic mechanisms leading to hyperexcitability in epilepsy and hemiplegic migraine

PLoS Comput Biol. 2021 Jul 27;17(7):e1009239. doi: 10.1371/journal.pcbi.1009239. eCollection 2021 Jul.


Loss of function mutations of SCN1A, the gene coding for the voltage-gated sodium channel NaV1.1, cause different types of epilepsy, whereas gain of function mutations cause sporadic and familial hemiplegic migraine type 3 (FHM-3). However, it is not clear yet how these opposite effects can induce paroxysmal pathological activities involving neuronal networks' hyperexcitability that are specific of epilepsy (seizures) or migraine (cortical spreading depolarization, CSD). To better understand differential mechanisms leading to the initiation of these pathological activities, we used a two-neuron conductance-based model of interconnected GABAergic and pyramidal glutamatergic neurons, in which we incorporated ionic concentration dynamics in both neurons. We modeled FHM-3 mutations by increasing the persistent sodium current in the interneuron and epileptogenic mutations by decreasing the sodium conductance in the interneuron. Therefore, we studied both FHM-3 and epileptogenic mutations within the same framework, modifying only two parameters. In our model, the key effect of gain of function FHM-3 mutations is ion fluxes modification at each action potential (in particular the larger activation of voltage-gated potassium channels induced by the NaV1.1 gain of function), and the resulting CSD-triggering extracellular potassium accumulation, which is not caused only by modifications of firing frequency. Loss of function epileptogenic mutations, on the other hand, increase GABAergic neurons' susceptibility to depolarization block, without major modifications of firing frequency before it. Our modeling results connect qualitatively to experimental data: potassium accumulation in the case of FHM-3 mutations and facilitated depolarization block of the GABAergic neuron in the case of epileptogenic mutations. Both these effects can lead to pyramidal neuron hyperexcitability, inducing in the migraine condition depolarization block of both the GABAergic and the pyramidal neuron. Overall, our findings suggest different mechanisms of network hyperexcitability for migraine and epileptogenic NaV1.1 mutations, implying that the modifications of firing frequency may not be the only relevant pathological mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology
  • Animals
  • Computational Biology
  • Cortical Spreading Depression / physiology
  • Disease Models, Animal
  • Epilepsy / genetics*
  • Epilepsy / physiopathology
  • Female
  • GABAergic Neurons / physiology
  • Gain of Function Mutation
  • Humans
  • Interneurons / physiology
  • Ion Channel Gating / physiology
  • Loss of Function Mutation
  • Male
  • Mathematical Concepts
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Migraine Disorders / genetics*
  • Migraine Disorders / physiopathology
  • Models, Neurological*
  • Mutation*
  • NAV1.1 Voltage-Gated Sodium Channel / deficiency
  • NAV1.1 Voltage-Gated Sodium Channel / genetics*
  • NAV1.1 Voltage-Gated Sodium Channel / physiology
  • Patch-Clamp Techniques
  • Pyramidal Cells / physiology
  • Somatosensory Cortex / physiopathology
  • Voltage-Gated Sodium Channel beta-1 Subunit / deficiency
  • Voltage-Gated Sodium Channel beta-1 Subunit / genetics
  • Voltage-Gated Sodium Channel beta-1 Subunit / physiology


  • NAV1.1 Voltage-Gated Sodium Channel
  • SCN1A protein, human
  • Scn1b protein, mouse
  • Voltage-Gated Sodium Channel beta-1 Subunit

Supplementary concepts

  • Migraine, Familial Hemiplegic, 3

Grants and funding

UCAJEDI (, ANR-15-IDEX-01, to MM), Laboratory of Excellence “Ion Channel Science and Therapeutics” - LabEx ICST (, ANR-11-LABX-0015-01, to MM), Foundation Famiglie Dravet Onlus (, FDO-2018, to MM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.