scholarly journals 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

2021 ◽  
Vol 17 (7) ◽  
pp. e1009239
Author(s):  
Louisiane Lemaire ◽  
Mathieu Desroches ◽  
Martin Krupa ◽  
Lara Pizzamiglio ◽  
Paolo Scalmani ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Pyramidal Neuron ◽  
Firing Frequency ◽  
Extracellular Potassium ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Hemiplegic Migraine ◽  
Potassium Accumulation ◽  
Depolarization Block ◽  
Voltage Gated

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.

scholarly journals Gain-of-function mutation of a voltage-gated sodium channel NaV1.7 associated with peripheral pain and impaired limb development

2017 ◽  
Vol 292 (22) ◽  
pp. 9262-9272 ◽  
Author(s):  
Brian S. Tanaka ◽  
Phuong T. Nguyen ◽  
Eray Yihui Zhou ◽  
Yong Yang ◽  
Vladimir Yarov-Yarovoy ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Limb Development ◽  
Gain Of Function ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Peripheral Pain ◽  
Impaired Limb

scholarly journals Molecular pathobiology of aspirin responsive erythromelalgia in thrombocythemia and incurable inherited erythermalgia in Nav1.7mutated neuropathy

2017 ◽  
Vol 2 (2) ◽  
Keyword(s):  
Sodium Channel ◽  
Original Description ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Peripheral Neurons ◽  
Burning Pain ◽  
Arterial Circulation ◽  
Incurable Disease ◽  
Distinct Disease ◽  
Disease Entities

The original description of erythromelalgia of Mitchell has been separated into three distinct disease entities of aspirin responsive erythromelalgia in thrombocythemia, incurable congenital dominant primary erythermalgia (PE), and aspirin resistant secondary erthermalgia. Aspirin responsive platelet-mediated erythromelalgic and thrombotic processes in the end-arterial circulation of toes or fingers has been discovered as a distinct arterial thrombophilic disease entity (Sticky Platelet Syndrome) in acquired and congenital thrombocythemia due to gain of function mutations in the JAK2, TPO, MPL and CALR genes. PE is a congenital dominant incurable disease with symmetric bilateral localization of red congestion and burning pain in legs with relative sparing of the toes, which spontaneously arises in childhood or adolecence and persists life long in adults. Incurable PE has been discovered as a dominant neuropathic pain disorder caused by hyperexcitibility of the sodium channel alpha subunit Nav1.7 protein located in dorsal root ganglions and nocireceptive peripheral neurons due to gain of function mutations in the SCN9A gene on chromosome 2q coding for the Nav1.7 sodium channel. Recessive chronic insensitivity for pain (CIP) is caused by homozygous or double heterozygous loss of function mutations of the SCN9A gene and loss of Nav1.7 sodium channel excitibility

scholarly journals Astrocyte Ca2+ Signaling is Facilitated in an Scn1a+/− Mouse Model of Dravet Syndrome

2021 ◽  
Author(s):  
Kouya Uchino ◽  
Wakana Ikezawa ◽  
Yasuyoshi Tanaka ◽  
Masanobu Deshimaru ◽  
Kaori Kubota ◽  
...  
Keyword(s):  
Mouse Model ◽  
Sodium Channel ◽  
Epileptic Encephalopathy ◽  
Dravet Syndrome ◽  
Heterozygous Mutation ◽  
Loss Of Function ◽  
Cell Type ◽  
Voltage Gated ◽  
A Subunit ◽  
The Brain

Dravet syndrome (DS) is an infantile-onset epileptic encephalopathy. More than 80% of DS patients have a heterozygous mutation in SCN1A, which encodes a subunit of the voltage-gated sodium channel, Nav1.1, in neurons. The roles played by astrocytes, the most abundant glial cell type in the brain, have been investigated in the pathogenesis of epilepsy; however, the specific involvement of astrocytes in DS has not been clarified. In this study, we evaluated Ca2+ signaling in astrocytes using genetically modified mice that have a loss-of-function mutation in Scn1a. We found that the slope of spontaneous Ca2+ spiking was increased without a change in amplitude in Scn1a+/− astrocytes. In addition, ATP-induced transient Ca2+ influx and the slope of Ca2+ spiking were also increased in Scn1a+/− astrocytes. These data indicate that perturbed Ca2+ dynamics in astrocytes may be involved in the pathogenesis of DS.

Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine

The Lancet ◽  
2005 ◽  
Vol 366 (9483) ◽  
pp. 371-377 ◽  
Author(s):  
Martin Dichgans ◽  
Tobias Freilinger ◽  
Gertrud Eckstein ◽  
Elena Babini ◽  
Bettina Lorenz-Depiereux ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Familial Hemiplegic Migraine ◽  
Hemiplegic Migraine ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated

scholarly journals Characterization of a gene-trap knockout mouse model of Scn2a encoding voltage-gated sodium channel Nav1.2

2020 ◽  
Author(s):  
Muriel Eaton ◽  
Jingliang Zhang ◽  
Zhixiong Ma ◽  
Anthony C. Park ◽  
Emma Lietzke ◽  
...  
Keyword(s):  
Mouse Model ◽  
Sodium Channel ◽  
Knockout Mouse ◽  
Large Scale ◽  
Autism Spectrum ◽  
Gene Trap ◽  
Fecal Excretion ◽  
Loss Of Function ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated

ABSTRACTRecent large-scale genomic studies have revealed SCN2A as one of the most frequently mutated gene in patients with neurodevelopmental disorders including autism spectrum disorder and intellectual disability. SCN2A encodes for voltage-gated sodium channel isoform 1.2 (Nav1.2), which is mainly expressed in the central nervous system and responsible for the propagation of neuronal action potentials. Homozygous knockout (null) of Scn2a is perinatal lethal, whereas heterozygous knockout of Scn2a results in mild behavior abnormalities. To achieve a more substantial, but not complete, reduction of Scn2a expression, we characterized a Scn2a deficient mouse model using a targeted gene trap knockout (gtKO) strategy to recapitulate loss-of-function SCN2A disorders. This model produces viable homozygous mice (Scn2agtKO/gtKO) that can survive to adulthood, with markedly low but detectable Nav1.2 expression. Although Scn2agtKO/gtKO adult mice possess normal olfactory, taste, hearing, and mechanical sensitivity, they have decreased thermal and cold tolerance. Innate behaviors are profoundly impaired including impaired nesting, marble burying, and mating. These mice also have increased food and water intake with subsequent increases in fecal excretion of more but smaller fecal boli. This novel Scn2a gene trap knockout mouse thus provides a unique model to study pathophysiology associated with Scn2a deficiency.

scholarly journals Myasthenic congenital myopathy from recessive mutations at a single residue in NaV1.4

Neurology ◽  
2019 ◽  
Vol 92 (13) ◽  
pp. e1405-e1415 ◽  
Author(s):  
Nathaniel Elia ◽  
Johanna Palmio ◽  
Marisol Sampedro Castañeda ◽  
Perry B. Shieh ◽  
Marbella Quinonez ◽  
...  
Keyword(s):  
Sodium Channel ◽  
The United States ◽  
Congenital Myopathy ◽  
Compound Heterozygous ◽  
Missense Mutations ◽  
Recessive Inheritance ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Recessive Mutations ◽  
Targeted Mutation

ObjectiveTo identify the genetic and physiologic basis for recessive myasthenic congenital myopathy in 2 families, suggestive of a channelopathy involving the sodium channel gene, SCN4A.MethodsA combination of whole exome sequencing and targeted mutation analysis, followed by voltage-clamp studies of mutant sodium channels expressed in fibroblasts (HEK cells) and Xenopus oocytes.ResultsMissense mutations of the same residue in the skeletal muscle sodium channel, R1460 of NaV1.4, were identified in a family and a single patient of Finnish origin (p.R1460Q) and a proband in the United States (p.R1460W). Congenital hypotonia, breathing difficulties, bulbar weakness, and fatigability had recessive inheritance (homozygous p.R1460W or compound heterozygous p.R1460Q and p.R1059X), whereas carriers were either asymptomatic (p.R1460W) or had myotonia (p.R1460Q). Sodium currents conducted by mutant channels showed unusual mixed defects with both loss-of-function (reduced amplitude, hyperpolarized shift of inactivation) and gain-of-function (slower entry and faster recovery from inactivation) changes.ConclusionsNovel mutations in families with myasthenic congenital myopathy have been identified at p.R1460 of the sodium channel. Recessive inheritance, with experimentally established loss-of-function, is a consistent feature of sodium channel based myasthenia, whereas the mixed gain of function for p.R1460 may also cause susceptibility to myotonia.

Sodium Channels and Pain

2019 ◽  
pp. 232-262
Author(s):  
Theodore R. Cummins ◽  
Stephen G. Waxman ◽  
John N. Wood
Keyword(s):  
Ion Channels ◽  
Drug Development ◽  
Sodium Channel ◽  
Sodium Channels ◽  
Physiological Role ◽  
Channel Blockers ◽  
Loss Of Function ◽  
Sodium Channel Blockers ◽  
Voltage Gated ◽  
Damage Sensing

Electrical excitability in nerve and muscle depends on the action of voltage-gated sodium-selective ion channels. It is now known that there are nine such ion channels; intriguingly, three of them, Nav1.7, Nav1.8, and Nav1.9, are found relatively selectively in peripheral damage-sensing neurons. Local anesthetics are sodium channel blockers that have proved to be excellent analgesics. However, their systemic use is limited by side effects. Because it is known that peripheral damage-sensing sensory neurons are required to drive most pain conditions, there have been many attempts to target peripheral sodium channels for pain relief. Human genetic advances have supported the idea that multiple sodium channel subtypes are good analgesic drug targets. Human monogenic gain-of-function mutations in Nav1.7, Nav1.8, and Nav1.9 cause ongoing pain conditions, while loss-of-function Nav1.7 mutations produce insensitivity to pain. This compelling genetic evidence has inspired a large number of drug development programs aimed at developing analgesic subtype-selective sodium channel blockers. This article reviews the structure and physiological role of voltage-gated sodium channels and describes recent advances in understanding the contribution of sodium channel isoforms to different pain states. Also described are mechanistic studies aimed at better understanding routes to drug development and the potential of gene therapy in therapeutic approaches to pain control. Two decades of sodium channel–targeted drug development have yet to produce a clinical breakthrough, but recent progress holds promise that useful new analgesics are on the horizon.

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