In:
PLOS Computational Biology, Public Library of Science (PLoS), Vol. 17, No. 7 ( 2021-7-27), p. e1009239-
Abstract:
Loss of function mutations of SCN1A , the gene coding for the voltage-gated sodium channel Na V 1.1, 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 Na V 1.1 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 Na V 1.1 mutations, implying that the modifications of firing frequency may not be the only relevant pathological mechanism.
Type of Medium:
Online Resource
ISSN:
1553-7358
DOI:
10.1371/journal.pcbi.1009239
DOI:
10.1371/journal.pcbi.1009239.g001
DOI:
10.1371/journal.pcbi.1009239.g002
DOI:
10.1371/journal.pcbi.1009239.g003
DOI:
10.1371/journal.pcbi.1009239.g004
DOI:
10.1371/journal.pcbi.1009239.g005
DOI:
10.1371/journal.pcbi.1009239.g006
DOI:
10.1371/journal.pcbi.1009239.g007
DOI:
10.1371/journal.pcbi.1009239.g008
DOI:
10.1371/journal.pcbi.1009239.g009
DOI:
10.1371/journal.pcbi.1009239.g010
DOI:
10.1371/journal.pcbi.1009239.g011
DOI:
10.1371/journal.pcbi.1009239.g012
DOI:
10.1371/journal.pcbi.1009239.g013
DOI:
10.1371/journal.pcbi.1009239.t001
DOI:
10.1371/journal.pcbi.1009239.t002
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2193340-6
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