Open access peer-reviewed chapter

Genetic Defects of Voltage-Gated Sodium Channel α Subunit 1 in Dravet Syndrome and the Patients’ Response to Antiepileptic Drugs

Written By

Tian Li

Submitted: 28 November 2017 Reviewed: 12 March 2018 Published: 10 October 2018

DOI: 10.5772/intechopen.76390

From the Edited Volume

Ion Channels in Health and Sickness

Edited by Kaneez Fatima Shad

Chapter metrics overview

1,328 Chapter Downloads

View Full Metrics


In the past decade, hundreds of mutations have been found in the SCN1A (sodium voltage-gated channel α subunit 1) gene in the epileptic patients. The functioning of the SCN1A gene products is intensively studied in the neuroscience field. The loss-of-function mutations of the SCN1A gene are the causative factor of Dravet syndrome, an intractable epilepsy syndrome. With the loss-of-function Nav1.1 (the protein encoded by SCN1A gene), the selective dysfunction of the inhibitory parvalbumin (PV) interneurons impairs the balance of excitatory and inhibitory synaptic inputs to the downstream neurons, and causes the hyperexcitability of the neuronal network. The underlying mechanism is that the axon initial segments (AISs) of inhibitory parvalbumin interneurons predominantly express Nav1.1, particularly in the proximal end of the AISs. The deficiency of Nav1.1 weakens the excitability of the inhibitory parvalbumin neurons and leads to the hyperexcitability of the neuronal network. The sodium channel blockers, one category of the antiepileptic drugs (AEDs) that specifically block the activity of VGSCs, may potentially worsen the defect of Nav1.1 of the PV interneurons in the patients with the SCN1A gene loss-of-function mutations, aggravate the clinical manifestation, and increase the seizure frequency of those patients.


  • epilepsy
  • Dravet syndrome
  • voltage-gated sodium channel
  • axon initial segment
  • interneuron

1. Introduction

Voltage-gated sodium channels (VGSCs) play an essential role in the generation of the action potentials, which are the primary way for the communication between the excitable cells, particularly the neurons. The action potential is the fast method to collect the afferent sensory information and to relay the efferent motor commands in the nervous system. The pathways to transfer the action potentials rely on the organized expression and the proper functioning of VGSCs [1]. The genetic mutations that cause the defected expression of VGSCs or the malfunction of the altered VGSC gene products impair the physiological function of conduction pathway [2], nerve nuclei [3], and cortical neurons [4]. Epilepsy is a common multifactorial neurological disease that is caused by both environmental and genetic factors [5]. Several ion-channel genes are evidently associated with epilepsy, such as SCN1A [6], SCN2A (sodium voltage-gated channel α subunit 2) [7], SCN8A (sodium voltage-gated channel α subunit 8) [8], GABRA1 (gamma-aminobutyric acid type A receptor α 1 subunit), GABRG2 (gamma-aminobutyric acid type A receptor γ2 subunit) [9], and KCNA2 (potassium voltage-gated channel subfamily A member 2) [10]. Those genes predominantly control at least one critical event in a specific neuron type or/and a particular subcellular region during the physiological functioning of the neurons. The irreversible dysfunction of those gene products leads to the permanent pathological alteration of the targeted neurons and increases the susceptibility to seizures.


2. VGSC α subunit 1 and Dravet syndrome

Nav1.1 existing in the majority in the brain and was labeled at the soma and dendrites of the neurons in the early studies, referred as Na + channel subtype RI, or Type I Na(+) channel alpha-subunit [11, 12]. Nowadays, more than 1000 mutations [13] have been found in the SCN1A genes. They have been believed as the causative factors of generalized epilepsy with febrile seizure plus (GEFS+) [14], Dravet syndrome (severe myoclonic epilepsy of infancy—SMEI) [15], and migraine [16]. The SCN1A gene could be called as “an epilepsy gene” because of its close relationship with febrile seizures and the epilepsies with antecedent febrile seizures [13]. Dravet syndrome has been intensively studied within SCN1A gene mutations, the related functional analysis [6, 17], and the high phenotype-genotype correlations to SCN1A gene [18]. It is a rare disease of 1-to-40,000 incidence in the USA at estimate and 1-per-15,700 incidence in northern California with evidence [19]. The debilitating clinical progress goes from the “febrile stage” in the first year of life, the “worsening stage” until the age of 6 years, to the “stabilization stage” in the rest of life [20]. The clinical case may have the family history of epilepsy or febrile seizures, no previous medical history (an apparently normal baby), and the generalized or unilateral febrile seizures beginning in the first year followed by myoclonic jerks, partial seizures, atypical absence, and status epilepticus. The patients progressively lose the neurological functioning, such as retarded psychomotor development, ataxia, pyramidal signs, interictal myoclonus, intellectual deficiency or cognitive impairment, and personality disorders [21]. A French pediatrician, Dr. Charlotte Dravet, first described the rare disease in 1978 [22], and in 2001, Lieve Claes team in Belgium found seven SCN1A gene mutations in SMEI patients, including four frameshift and truncation mutations (c.657-658delAG, c.3299-3300insAA, c.5010-5013delGTTT, and c.5536-5539delAAAC), one nonsense mutation (c.664C>T), one splice donor mutation (IVS22+1G>A), and one missense mutation (c.2956C>T) [15]. The subsequent genotyping studies indicated that the SCN1A gene truncation mutations appeared with the higher frequency in Dravet syndrome than in the milder phenotype of febrile seizure-related epilepsy, and furthermore, the cognitive function impairment of the SCN1A-positive epilepsy patients also associated with the truncation variants, regardless of age at seizure onset [23]. Those truncation mutations severely alter the molecular structure of sodium channel, reduce the expression amount of the SCN1A gene products, and hence severely impact the Nav1.1-VGSC functioning in the neurons. The underlying pathogenic mechanism of one-allele truncation could be due to the haploinsufficiency (the loss of the half amount of Nav1.1) [24] or a dominant-negative effect that represents the mutated proteins (truncated Nav1.1) negatively affect wild-type products (normal allele-expressed Nav1.1) [25]. However, the truncated Nav1.1 protein in the human brain sample of a patient with Dravet syndrome was not detected, while the mRNA of both the wild-type and the truncation mutations was equally expressed. It was explained as the endoplasmic reticulum-associated degradation of the misfolded or misassembled protein caused the absence of the truncated Nav1.1 protein [26]. Therefore, the lower expression of the Nav1.1 protein, the haploinsufficiency of SCN1A gene, should be the main pathogenesis of SCN1A truncation mutations. The remaining mutations of SCN1A gene causing Dravet syndrome are the missense and splice-site mutations that mistakenly code the amino acids building the pore-forming region of VGSC [27] and cause the severe impairment of the function and electrophysiological properties of the Nav1.1 protein (VGSC α subunit 1) [28, 29, 30].

Both the haploinsufficiency and the pore-forming mutations of SCN1A gene impact the VGSC function severely because structurally the Nav1.1 protein constructs the main part of VGSC complex. This type of sodium channel is made up of a large pore-forming glycosylated α subunit and one or two small β subunits non-covalently (β1 or β3) or covalently (β2 or β4) associated with the large α subunit. The α subunit is coded by SCN1A-SCN11A gene (Nav1.1-Nav1.9 protein) and responsible for the generation of transmembrane sodium current. The β subunits regulate the electrophysiological properties of sodium current (the gating and kinetics of α subunits) and the subcellular location or expression of α subunit [31]. Those mutations disable the main part of VGSC, α subunit, by either the insufficient amount of subunit for the complex resembling or the structurally altered subunit to make the malfunctioning complex. The primary structure of the VGSC α subunit contains four internally repeated transmembrane domains (I–IV). Each domain includes six α-helical transmembrane segments (S1–S6). The S1–S4 segments are the voltage-sensing module, and the S5–S6 segments are the pore-forming module (D400, E755, K1237, and A1529 in each of four homologous domains, forming part of the selectivity filter [32]). Nine members of VGSC α subunits (Nav1.1–Nav1.9) have been identified with similar complex structure and functional properties [33]. Nav1.1 is tetrodotoxin (TTX)-sensitive and could be blocked by nanomolar concentrations of TTX [34]. Nav1.1, Nav1.2 (SCN2A), Nav1.3 (SCN3A), and Nav1.6 (SCN8A) primarily locate in central nervous system and are the primary subtypes of VGSCs in the neurons of brain and spinal cord [35]. Four subtypes of VGSC α subunits in the central nervous system express in the specific neuron types and the specific subcellular location [36, 37].


3. Animal models and pathogenic mechanism of Dravet syndrome

Based on the genotyping results that the SCN1A-gene truncation mutations are found in the large percentage of patients with Dravet syndrome [18], the scientists produce the genetic models to disrupt the SCN1A gene by truncation mutations. They successfully duplicate the clinical features in mouse models of Dravet syndrome, such as spontaneous and frequent seizures, impaired neurological function, and premature death [4, 38, 39]. Yu et al. at the University of Washington, USA, first replaced the last exon (Exon 26) of SCN1A gene of 129/SvJ and C57BL/6 mice with neomycin-resistance gene cassette to make the truncation at the domain IV, S3 segment of Nav1.1 protein. By measuring whole-cell sodium currents of the dissociated neurons, the authors found a substantial decrease in the sodium current amplitude and other significant alteration of electrophysiological features, which indicated the reduced amount of the functional VGSCs in Scn1a−/− and Scn1a+/− interneurons. They also confirmed that in those GABAergic inhibitory interneurons the VGSC subtype Nav1.3 was upregulated to compensate the reduced functional Nav1.1 protein, without the apparent increase of Nav1.2 and Nav1.6 [4]. The group of Mistry at the Vanderbilt University, USA, generated another SCN1A gene truncation mice in 2014 by disrupting Exon 1 of the SCN1A gene. They measured the electrophysiological features of acutely dissociated hippocampal neurons and found that the sodium channel density was lower in GABAergic interneurons of the Scn1a+/− mice. Furthermore, the sodium channel density in excitatory pyramidal neurons of Scn1a+/− mice was also elevated, which potentially correlated with age-dependent lethality. Although the phenotype severity was variable due to the factors of strain and age of mice with Dravet syndrome, the findings first emphasized the contribution of pyramidal neuron hyperexcitability during the pathological process in the study of animal model [38]. Both of the studies point out that the imbalance of electrophysiological activities of the excitatory (pyramidal neurons) and the inhibitory neurons (GABAergic interneurons) is the fundamental pathogenesis to cause the intractable seizures in mice with Dravet syndrome that had the SCN1A gene truncation mutations.

Furthermore, the Ogiwara group in Japan provided the results from an SCN1A truncation knock-in mouse model, which displayed the specific subcellular region of Nav1.1 deficiency in those dysfunctional inhibitory neurons. By inserting the nonsense mutation R1407X into mouse SCN1A gene, the authors found that the truncated Nav1.1 protein was not detectable in either Scn1aRX/RX or Scn1a+/RX knock-in mice. In the neocortex of those developing mouse brain, only a subpopulation of the neocortical neurons, the parvalbumin-positive interneurons (PV neurons), had the Nav1.1 immunostaining signals, predominantly at the axon initial segments (AISs). Consequently, the Scn1a+/RX neocortical PV interneuron (GAD67+), fast-spiking interneurons, displayed the spike amplitude decrement during prolonged spike trains [6, 39]. That important study proved the specific functional defect of the PV neurons and the critical pathophysiological role of the PV neurons in Dravet syndrome. Moreover, in an in-vivo animal study, using the advanced techniques, such as optogenetics, local field potential, and multiunit activity signals recording, the authors surprisingly found that the spontaneous cortical activity of Scn1a+/− mice did not alter in vivo. Although after sacrificing those mice, they could recognize the seizure-related pathological changes in the brain slices, such as the hypoexcitability of the parvalbumin and somatostatin interneurons, the rapid propagation of epileptiform activity, and the pathogenic synaptic adaptions [40]. Therefore, we could reason that the interneuron hypoexcitability should exist much earlier than the electroencephalography (EEG)-positive findings in the patients with Dravet syndrome.

The other type of SCN1A gene mutations causing Dravet syndrome is the missense mutation in the pore-forming region of VGSC. Another group in Japan, using gene-driven ENU mutagenesis technique, generated Scn1a-targeted rats carrying a missense mutation N1417H miscoding the amino acid in the third pore region of VGSC [29]. The clinical feature of the N1417H rat was milder than that of truncation Scn1a mouse models. The rat had neither spontaneous seizures nor apparent pathological abnormality in the brain in the earlier life, but at postnatal week 5, after a hot water bath about 3.5 min, the rats exhibited clonic seizures. The susceptibility to hyperthermia-induced seizures increased with age. The hippocampal GABAergic interneurons of the N1417H rats were hypoexcitable with the reduced action potential amplitude. The authors believed that the clinical phenotype of the N1417H rat was close to that of generalized epilepsy with febrile seizure plus (GEFS+) [41]. However, the common pathogenic mechanism of the truncation mutations and the pore-forming region mutations of Nav1.1 is the selective interneuron dysfunction and hypoexcitability due to the Nav1.1 deficiency or malfunction. The results from the study of the N1417H rat enhance the hypothesis that the selective impairment of the PV interneurons is the primary pathogenesis of febrile seizure–related epilepsy syndrome, the clinical spectrum from GEFS+ to Dravet syndrome [18].


4. Inhibitory interneurons and the features for their specialties

During the processing of the neuronal activities in the central nervous system, the simultaneous excitation and inhibition assure the proper excitability of the neuronal network and the precise control of the neuronal functions. Inhibition in the cortex is generated by the GABAergic neurons, which make up about 20% of the cortical neuronal population. Compared with the pyramidal cells (excitatory neurons), they have the smaller size and much shorter-range projects of the axon to form the local circuit with the nearby neurons and layers [42]. The interneurons could generate the long-lasting currents, the faster reaction to stimuli, and the higher-frequency signal transmission. The inhibition in a neuronal microcircuit could apply at the right millisecond (timing) and with the precise amount (dosing) exactly matching the inhibitory demand [42, 43]. The defects of GABAergic neuronal function have been identified as the contributive factors to the neuronal diseases, such as epilepsy, schizophrenia, and autism spectrum disorders [44, 45]. The cell therapy strategy of the GABAergic neurons for epilepsy was applied in several significant studies of epileptic model and stem cells [44, 46]. In the studies of animal models of Dravet syndrome, the constitutive Na1.1 knockout selectively impacted the functioning of the inhibitory parvalbumin interneurons, spared the detectable dysfunction of the excitatory neurons, and caused by the imbalance of excitation and inhibition, which led to the spontaneous and intractable seizures [4, 38, 39]. On the background of the Nav1.1 knockout specifically in the PV neurons, the addition of Nav1.1 knockout specifically in the excitatory neurons could alleviate the clinical manifestation of Dravet syndrome [6] and potentially re-balance the excitatory and inhibitory neuronal activity. Based on those results, we can understand that the balancing status of inhibitory neurons and excitatory neurons functioning is the determinant of the clinical phenotypes of Drave syndrome.

The several types of inhibitory interneurons are called as “basket” cells, “chandelier” cells, and “Martinotti” cells due to their morphological features. Because of their morphological advantages, they connect and inhibit the particular compartment of principal neurons [42]. The “basket” cells have the highly branched axons that innervate the target somas and the proximal dendrites of pyramidal neurons, as the axonal branches appear like baskets surrounding the pyramidal neurons. In hippocampus CA1, the parvalbumin-expressing basket cells (PVBCs, 26% of CA1 interneurons) are more than the cholecystokinin-expressing basket cells (CCKBCs, 12% of CA1 interneurons) [47]. The PVBCs place 99% output to connect the pyramidal cells and the rest 1% output to form the gap junctions and reciprocal synaptic connections onto themselves or other interneurons generating gamma oscillation [48, 49]. The “chandelier” cells that are also parvalbumin positive have the “cartridges” shape of the axonal arbors that selectively inhibit the AISs of pyramidal cells, and hence they are also called the axon-axonic cells providing precise control of the action potential generation of pyramidal cells [48, 50, 51]. The axon-axonic cells represent about 15% of all PV hippocampal interneurons [47]. The “Martinotti” cells target the apical dendritic tuft and express the somatostatin and calbindin but not parvalbumin or vasoactive intestinal peptide (VIP) [52]. In the hippocampus, the rest of PV cells is “Bistratified” cells, which represent about 25% of PV hippocampal interneurons with the PV-immunosignal on the somatodendritic compartments. In the PVBCs, the Na+ channels are sparse in the dendrites where K+ channels predominate. The Na+ channels cluster at the AIS of PVBCs. In fact, 99% of PVBC Na+ channels are located in the axonal compartment [53]. The unique feature of the high-density distribution of Na+ channels at the PVBC AISs determines the fast-spiking pattern of the PVBCs, which typically generate uniform, non-changing, and high-frequency discharge [54].


5. AIS and VGSC

Axon initial segment (AIS) contains the high density of sodium and potassium channels; the scaffolding protein ankyrin G (AnkG), βIV spectrin, and extracellular matrix–binding protein neurofascin; and the ion channel–associated protein FGF14 (fibroblast growth factor 14). Those are necessary to help the sodium channels locate and cluster at the AIS [55]. The AIS has the lowest threshold for action potential initiation because of the highest density of sodium channels when compared with somatodendritic compartment [53]. The proper functioning of AIS is essential for action potential initiation and adaptive cell excitability of both pyramidal cells (excitatory neurons) and GABAergic interneurons (inhibitory neurons). Many factors regulate the function of the sodium channels at the AIS [55, 56]. First, the distinctive VGSC α subunit types express in specific neuronal types and the particular regions of AIS. In the human brain tissue, the fluorescence signals of Nav1.1 have been found at the thinly AnkG-labeled AIS, which putatively belongs to the interneurons, while Nav1.2 and Nav1.6 are located at the AISs of human cortical pyramidal cells [51]. Nav1.6, the low-threshold sodium channel subtype, accumulates at the distal end of AIS of cortical pyramidal cells, which is responsible for generating the action potentials. The high-threshold Nav1.2 locates at the proximal end of AIS of cortical pyramidal cells, which regulates the action potential backpropagation [57]. The Nav1.1 has been found at the proximal end of AIS of cortical and cerebellar interneurons and the axons of main olfactory bulb neurons. The Nav1.1 immunosignals predominantly outline the axons of the parvalbumin-positive neurons [58]. The action potential threshold of Nav1.6 is more hyperpolarized (15–25 mV lower) than that of both Nav1.2 and Nav1.1. Unlike Nav1.6 more likely producing a persistent current, Nav1.1 and Nav1.2 show the apparent use-dependent inactivation (higher than 20 Hz) [59, 60]. Therefore, the accumulated Nav1.6 at the distal end of the AIS facilitates the action potential initiation, while Nav1.2 and Nav1.1 subunits gathering at the proximal end of AIS prevent the high-frequency firing of nerve cells backward.

Second, the molecule complex at AIS, composed of the ion channels (Kv1, T-type Ca2+ channel) and ligands (FGF14, VGSC β subunit 1, and βIV spectrin), directly or indirectly cooperates with Na+ channel and regulates the neuronal excitability. FGF14 could directly interact with the C-terminal of VGSC α subunit (Nav1.1, Nav1.2, Nav1.6) in the transfected HEK293 cells [61]. The fgf14−/− mice showed the significantly reduced number of the PV interneurons, but the pyramidal neuron number was unchanged in the CA1 hippocampus region. This change cooperated with the reduced GAD67 immunosignals in PV cell soma, the reduced gamma oscillations in CA1 stratum radiatum layer, and the deficits in spatial working memory, which was displayed by the eight-arm maze test [62]. Because the FGF14 is a complementary protein of Nav1.1, Nav1.2, and Nav1.6 at the AIS [61, 63, 64], the pyramidal cells of the fgf14−/− mice should have been affected as well due to the loss of FGF14:Nav1.6 and FGF14:Nav1.2 complex. Why are the PV cells the first or most to be affected by FGF14 protein defect or the FGF14:Nav1.1 complex deficiency? What makes the FGF14:Nav1.1 critical for the excitability of the PV cells and finally impact on the number of the live PV cells? Similarly, the Nav1.1-predominant proximal end of the AIS only occupies a small part of the AIS of the PV cells, and why the Nav1.1 deficiency impairs the PV cell functions dramatically and causes the Dravet syndrome? We expect the promising studies and explanation in future. Other molecules in the AIS complex, such as VGSC β subunit and AnkG, have been recognized as the ligand or the anchoring protein to stabilize the VGSC α subunit and regulate their functions at the AIS [65, 66].

Third, the location and the size of the AIS can be adapted for the neuronal activity and the long-term plasticity. The longer AIS, the higher excitability of the neuron. The more proximal location of the AIS, the higher excitability of the neuron. The chronic depolarization of the dissociated neurons moved the AIS distally and then decreased the neuronal excitability. The dynamic regulation of the AIS location through activity-dependent structural reorganization relied on the activation of T-type voltage-gated calcium channels and the elevation of intracellular [Ca2+] [67]. On the other hand, the experiments to eliminate the sensory stimuli made the AIS longer with little change in Na+ channel density and ion channel composition at the AIS, which increased the whole cell Na+ current, and the neuronal excitability. However, those adaptive responses also depend on the neuronal types due to the distinctions of the AIS location of different neurons under the standard conditions [67]. In the PV interneurons, the action potentials are generated at 20 μm away from the soma at the AIS [53], which means the proximal part of the AIS of the PV neurons locates even closer than 20 μm since the action potential generates at the beginning of the distal part of the AIS. The AIS of the PV neurons locates more proximal than the AIS of pyramidal cells that has been observed at 20–60 μm from the soma by ankyrin G staining [68]. Using specific neuronal marker labeling, Höfflin et al. saw the AISs of the pyramidal neurons were significantly longer than that of the interneurons [69]. Based on those findings of the PV interneurons and their AISs, neuroscientists may have many interests in the regulatory mechanisms of Nav1.1 cooperative functioning and adaptive response to the neuronal activity, coupling with the dynamic plasticity of the PV interneuron AIS.

With the specialized output structures of PV interneurons (“basket” or “chandelier cartridge”), the interactions of the PV interneurons (PVBCs or chandelier cells) and the pyramidal cells, inhibitory synapses, are accordingly subject to the dynamic regulation of adaptive neuronal functioning and the AIS plasticity. The chandelier cell axon terminals only contact the AISs of pyramidal cells and have three to five boutons per cartridge. The innervation patterns are similar at different postnatal age. Multiple chandelier cells (four at estimate) connect one pyramidal cell, while one chandelier cell contacts 35–50% of pyramidal cells in the traversed area by its axonal arbor [70]. The inhibitory synapses exist in the innervation of a chandelier cell to the pyramidal cell by nature. The innervation could be visible by labeling the chandelier cells (pre-synaptic component) with the marker of GABA membrane transporter 1 (GAT1) or parvalbumin (PV) and labeling the post-synaptic pyramidal cell AIS with GABAA receptor α2 subunit. The structures and functioning status of those synapses keep updated to meet the dynamic developmental demands [71, 72] and are impacted in the specific areas by pathological conditions, such as epilepsy and schizophrenia [73, 74].


6. Treatment to Dravet syndrome and therapeutic response

Dravet syndrome is an intractable epileptic encephalopathy with the unfavorable outcome. The most commonly used AEDs for patients with Dravet syndrome include valproate, topiramate, benzodiazepines, stiripentol, and potassium bromide [22]. Because the high percentage of patients with Dravet syndrome have the SCN1A gene mutations [18], some AEDs should be avoided, such as the sodium channel blockers (lamotrigine [75] and carbamazepine [76]), to prevent the inhibition of the rest Nav1.1 functioning in PV interneurons. Guerrini et al. retrospectively reviewed 21 Dravet syndrome cases and found that 80% (17) patients with lamotrigine treatment showed >50% increase in seizure frequency for 2 months and then ceased the lamotrigine treatment [75]. In a large-sized (276 patients) study, Shi et al. showed the evidence that the treatment of carbamazepine to Dravet syndrome was either not effective (<50% seizure reduction) or worsening the clinical condition (>25% increase in seizure frequency) [76]. Considering the high percentage of SCN1A gene mutations in Dravet syndrome and the potential risk of worsening seizures by AEDs, the clinicians recommend a screening test to detect the SCN1A gene mutations for the suspected patients with Dravet syndrome (the initially normal infants suffering from prolonged, recurrent, febrile, and hemiclonic seizures induced by bathing). The purpose of the screening test is to optimize AEDs and rehabilitation therapy [77, 78] at the earlier stage of the disease. The test can be done with the direct sequencing of the coding exons of SCN1A gene or multiplex ligation-dependent probe amplification [79]. There are an increasing number of the adult patients with the intractable seizures, who finally are diagnosed with Dravet syndrome. They may retain the partial seizures,secondary generalized clonic-tonic seizures [80], and intellectual disability, which are all not the characteristic symptoms for the diagnosis of Dravet syndrome. It is not occasional that those underdiagnosed patients with Dravet syndrome have been treated with sodium channel blockers, such as carbamazepine and oxcarbazepine, for years. However, the attempt to withdraw the treatment of carbamazepine or oxcarbazepine from those adult patients is still risky for seizure frequency rebound, withdrawal-related seizure, and sudden death [81].

Valproate is the most frequently used AED to treat Dravet syndrome. Shi et al. found that 87% of SCN1A mutation patients and 78% of SCN1A negative patients were using valproate. About 52% of SCN1A mutation patients and 41% SCN1A negative patients responded to the valproate treatment (>50% reduction in seizure frequency). Bromide (potassium bromide and sodium bromide) was the most effective AED. About 41% SCN1A mutation patients and 21% SCN1A negative patients used bromide with 71% and 94% responder rate, respectively. The SCN1A negative patients had the significantly higher responder rate to bromide, when compared with SCN1A mutation patients [76]. Bromide therapy was usually used in combination with valproate (100%), topiramate (91%), clobazam (75%), levetiracetam (66%), and so on. After 3 months of treatment, 81% of patients (26/32) had >50% reduction in seizure frequency, and after 12 months of treatment, 47% of patients (15/32) still maintained >50% seizure reduction [82]. Verapamil add-on treatment was reported in two pediatric patients with Dravet syndrome. They gained the long-period (13 months and 20 months) seizure free with the verapamil dosage of 1.5 mg/kg/day. As a result of a long period of seizure free, the patient’s neurological and cognitive function improved significantly [83]. Levetiracetam add-on treatment was proved as an effective therapy to Dravet syndrome by an open-label clinical trial. The dose was titrated up to 50–60 mg/kg/day within 5- to 6-week up-titration phase and maintained in a 12-week evaluation phase. The responder rate ranged from 44.4 to 64.2% varied by the distinctive seizure types [84]. Stiripentol is one of the commonly used medications for Dravet syndrome. Because of its fair tolerability profile, stiripentol is frequently added within valproate and clobazam and maintained in the triple long-term therapy remedy (96% patients). However, the effectiveness of stiripentol is not ideal for seizure control. De Liso et al. evaluated 54 patients with Dravet syndrome after stiripentol maintenance at the dose of 35–50 mg/kg/day. They found that 96% of patients continued to have clonic or tonic-clonic seizures (38% of patients had the seizure frequency more than three times per month, 40% of patients remained seizure frequency once to three times per month, and the rest of patients remained yearly seizures) [85]. Balestrini and Sisodiya observed stiripentol add-on treatment in 13 patients with Dravet syndrome. Only 23% of patients (3/13) gained >50% reduction in seizure frequency, 23% of patients (3/13) showed seizure worsening, 23% of patients (3/13) showed no change, and 15% of patients (2/13) showed <50% reduction in seizure frequency [86]. Obviously, the responder rate or effectiveness of the pharmacological treatment of Dravet syndrome is not ideal. The clinicians also assessed the vagus nerve stimulation for Dravet syndrome treatment. Fulton et al. placed the vagus nerve stimulation for 12 patients with Dravet syndrome and assessed the seizure control after 6 months. Nine of them showed >50% reduction in generalized tonic-clonic seizures, and four of them showed the cognitive function improvement [87]. Neuroscientist screened the potential therapeutic agents and tested their effectiveness in vivo in the experimental setting. Scn1Lab zebrafish model was used for the fast drug screening for SCN1A-mutated Dravet syndrome. Baraban et al. applied the molecules in the swimming bath of the mutant or control zebrafish, tracked the swimming velocity and behaviors of the zebrafish, and identified clemizole that could inhibit seizure behavior and electrographic seizures of the mutant zebrafish [88]. Ohmori et al. found that the intraperitoneal methylphenidate could improve the behavior (hyperactivity, anxiety-like behavior, and spatial learning impairments) of N1417H-Scn1a mice and significantly suppress the hot bath-induced seizures [89]. Similar to the results from human case studies, the N1417H-Scn1a mice showed the good therapeutic response to potassium bromide (reduced seizure duration) without significant impairment in motor coordination [90].


7. Discussion

Epilepsy is a chronic neurological disease worldwide, which jeopardizes the patients’ lives, burdens the patients’ family and caregivers, and requires to be concerned with the increasing attention to the affordable therapies, the effectiveness of current treatment strategies, and the social support to the patients and the caregivers. The pharmaceutical therapy (the application of AEDs) is the most commonly used strategy to fight against epilepsy. However, 30% of epilepsy patients are resistant to the optimized AED treatment without obvious precipitating factors [95]. Dravet syndrome might be an intractable and adverse form of extremity, which requires the multiple AED remedy (Table 1) and resistant to many AEDs over time [22]. The two major mechanisms are responsible for the resistance to AEDs in chronic epilepsy. One is the desensitization or modification of the molecular targets of AEDs during the chronic pathological process (frequent and recurring seizures), and the other is the overexpression of multidrug transporters, such as P-glycoprotein [96]. The sodium channel blocker is one of the main classes of AEDs. The genetic polymorphisms of the molecular targets, VGSC α subunits, are significantly associated with AED resistance. The genetic variant of SCN2A IVS7-32A>G (rs2304016) did not alter the SCN2A mRNA expression quantity or the exon splicing but had statistically significant association with AED resistance [97]. The calcium channel is also the therapeutic target of some AEDs, such as retigabine and ethosuximide (ETS). The genetic association study of drug-resistant epilepsy in the Chinese Han population displayed that the specific haplotype of the gene-coding calcium voltage-gated channel subunit alpha1 A (CACNA1A) was the risk factor for AED resistance [98]. How do those polymorphisms facilitate the desensitization of the AED target? We still need the extended functional studies to reveal the underlying mechanism. For instance, a significant cell functional study of the human brain samples collected from the surgery of hippocampal sclerosis resection provided the evidence of one mechanism of AED resistance (the modification of the cellular target of AEDs). Some categories of AEDs (benzodiazepines and barbiturates) stimulate the gamma-aminobutyric acid (GABAA) receptor and increase the intracellular concentration of chloride and synaptic inhibition. However, the expected GABAergic response of the treated pyramid cells relies on the proper functioning and the normal expression profile of chloride transporters (Na-K-2Cl cotransporter NKCCl and K-Cl cotransporter KCC2). Otherwise, the GABAA receptor activation depolarize the postsynaptic compartments, which contributes to the epileptiform activity in the stimulated pyramidal cells. In fact, in the temporal lobe epilepsy biopsy tissue, a small group of pyramidal cells downregulated the expression of KCC2 and led to depolarizing the postsynaptic neurons [99]. Because Dravet syndrome would be treated intensively with multiple AEDs for a long time, the multifaceted mechanisms might involve the AED resistance during the disease development. They could be the pathological alteration of the target cells at cellular/molecular level (downregulation of KCC2 in the pyramidal cells) or the overexpression of multidrug transporter genes that code ATP-binding cassette transporters 1–4 (ABCB1-4) in the epileptogenic zone (hippocampal sclerosis) [100]. The research interests might arise from those points in the future neuroscience and epileptology fields.

Agent or medicationMain action for treatmentDosage in the treatmentResponder rate (>50% reduction)Retain period (year)Retain combination remedyAggravation rate (>25% increase)Cause of death (SE or SUDEP*)
Valproate (VPA)Na+ Ca+ channel ↓ GABA ↑ GLUT ↑ [91]30–50 mg/kg/d [92]52 and 41% [76]VPA + Br VPA + CZP + Br
VPA + CLB + Br [81]
SUDEP [92]
Topiramate (TPM)Na+ Ca+ channel ↓ GABA ↑ GLUT ↑ [91]7.5–15 mg/kg/d [92]57 and 33% [76]17% [82]
Clobazam (CLB)GABA ↑ [91]0.2–1 mg/kg/d [92]44 and 48% [76]VPA + Br VPA + CLB + Br [81]SUDEP [92]
Clonazepam (CZP)GABA ↑ [91]0.03–0.1 mg/kg/d [92]44 and 38% [76]VPA + Br VPA + CZP + Br [81]
Zonisamide (ZNS)Na+ Ca+ channel ↓ [91]36 and 38% [76]44% [82]
Phenobarbital (PHB)GABA ↑ [91]29 and 35% [76]
Phenytoin (PHT)Sodium channel blocker [91]10 and 29% [76]50% [82]
Stiripentol (STP)GABAergic enhancer [93]35–50 mg/kg/d [85]23% [86]5 [86]VPA + CLB CLB + TPM VPA + TPM [86]23% [86] 6% [82]
Bromide (Br)Stabilize the excitable membrane through hyperpolarization [94]30–70 mg/kg/d [76]
30–106 mg/kg/d [82]
71 and 94% [76]
81% [82]
2.5 [76]
2 [82]
VPA + Br VPA + CZP + Br
VPA + CLB + Br [76]
VPA + TPM + CLB [82]
Levetiracetam (LEV)Act as a neuromodulator50–60 mg/kg/d [84]44–64% [84]VPA + TPM + LEV [84]
VPA + CLB + LEV [84]
5% [82]
Lamotrigine (LTG)Sodium channel blocker [91]2.5–12.5mg/kg/d [75]5% (1/21) [75]14 m# [75]VPA + CZP + CLB [75]57% [82] 80% [75]SUDEP [92]
Carbamazepine (CBZ)Sodium channel blocker [91]200–900 mg/day [81]9% [76]0.9–>20 [81]VPA CLB STP ZNS LEV CLN TPM PHT [81]33% [81] 71% [82]
21% [76]
SUDEP, SE [81]
Oxcarbazepine (OXC)Sodium channel blocker [91]600–1200 mg/day [81]Withdrawal + complete stop0.1–>20 [81]VPA CBZ ZNS LEV CLN PHB [81]72% [82]SUDEP [81]
VerapamilVoltage-gated calcium channel blocker [83]1.5 mg/kg/d [83]2/2 [83]13–>20 m#VPA TPM PHT ETS [83]
ClemizoleH1 antagonist [88]100 μM swim bath (zebrafish)Significant reduce seizure behaviorSingle doseMonotherapy [88]
MethylphenidateIncrease dopamine release (rat) [89]0.5–2.0 mg/kg i.p. [89]Significant improvementSingle doseMonotherapy [89]

Table 1.

The commonly used AEDs and the experimental therapies that have been applied in the treatment of Dravet syndrome.

SUDEP, sudden unexpected death in epilepsy; SE, status epilepticus.

m: month.

ETS, ethosuximide.


8. Conclusions

Dravet syndrome, an intractable epilepsy syndrome, affects the initially normal infants with febrile or non-febrile seizures, myoclonic seizures, hemiclonic seizures, and developmental delay. The SCN1A gene mutations are frequently found in patients with Dravet syndrome with “severe” genotypes, such as truncation or pore-region missense mutations. The SCN1A haplodeficiency mice display spontaneous seizures, cognitive impairment, and premature death, similar to human clinical phenotype of Dravet syndrome. The electrophysiological findings indicate that the parvalbumin-expressing interneurons in those mice are dysfunctional and hypoexcitable. The selective dysfunction of PV interneurons causes the imbalance of excitatory and inhibitory control to the principal neurons and neuronal network. The immunostaining has confirmed that Nav1.1 highly expresses at the axon initial segment of PV interneurons. Due to the complex and dynamic plasticity of AIS and the adaptation response of ion channels to neuronal activity, the Nav1.1 functioning within the AIS plasticity of PV interneurons and mutant pathogenesis remains unknown and would bring out the intensive studies in future. Patients with Dravet syndrome are always treated with multiple AEDs with disappointing outcome (Table 1). The most commonly used and retained AED in the treatment is valproate. The most evidently effective medication is bromide. With the aim to optimize the pharmacological treatment and encourage the earlier intervention to neurological development, the early genetic screening test of SCN1A gene is recommended to the possible patients with Dravet syndrome. Patients with Dravet syndrome should avoid the sodium channel blockers to prevent greater extent inhibition of Nav1.1 function that potentially worsens the seizures. We expect that the more promising results would be generated in the experimental therapy studies of Dravet syndrome and provide the valuable resources to help the patients with Dravet syndrome and overcome the devastating disease.



The author greatly appreciates the financial support from Postdoctoral Startup Research Foundation of Guangzhou Human Resource Department (310109-011).


Conflict of interest

The author declares that there is no conflict of interest.


  1. 1. Kruger LC, Isom LL. Voltage-gated Na+ channels: Not just for conduction. Cold Spring Harbor Perspectives in Biology. 2016;8(6). pii: a029264. DOI: 10.1101/cshperspect.a029264
  2. 2. Hoeijmakers JG, Faber CG, Lauria G, Merkies IS, Waxman SG. Small-fibre neuropathies—Advances in diagnosis, pathophysiology and management. Nature Reviews. Neurology. 2012;8(7):369-379. DOI: 10.1038/nrneurol.2012.97
  3. 3. Chen K, Godfrey DA, Ilyas O, Xu J, Preston TW. Cerebellum-related characteristics of Scn8a-mutant mice. Cerebellum. 2009;8(3):192-201. DOI: 10.1007/s12311-009-0110-z. Epub 2009 May 8
  4. 4. Yu FH, Mantegazza M, Westenbroek RE, Robbins CA, Kalume F, Burton KA, et al. Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy. Nature Neuroscience. 2006;9(9):1142-1149. Epub 2006 Aug 20
  5. 5. Ferraro TN, Dlugos DJ, Buono RJ. Role of genetics in the diagnosis and treatment of epilepsy. Expert Review of Neurotherapeutics. 2006;6(12):1789-1800
  6. 6. Ogiwara I, Iwasato T, Miyamoto H, Iwata R, Yamagata T, Mazaki E, et al. Nav1.1 haploinsufficiency in excitatory neurons ameliorates seizure-associated sudden death in a mouse model of Dravet syndrome. Human Molecular Genetics. 2013;22(23):4784-4804. DOI: 10.1093/hmg/ddt331. Epub 2013 Aug 6
  7. 7. Shi X, Yasumoto S, Kurahashi H, Nakagawa E, Fukasawa T, Uchiya S, Hirose S. Clinical spectrum of SCN2A mutations. Brain & Development. 2012 Aug;34(7):541-545. DOI: 10.1016/j.braindev.2011.09.016. Epub 2011 Oct 24
  8. 8. Wagnon JL, Meisler MH. Recurrent and non-recurrent mutations of SCN8A in epileptic encephalopathy. Frontiers in Neurology. 2015 May;6:104. DOI: 10.3389/fneur.2015.00104. eCollection 2015
  9. 9. Hirose S. Mutant GABA(A) receptor subunits in genetic (idiopathic) epilepsy. Progress in Brain Research. 2014;213:55-85. DOI: 10.1016/B978-0-444-63326-2.00003-X
  10. 10. Syrbe S, Hedrich UBS, Riesch E, Djémié T, Müller S, Møller RS, et al. De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. Nature Genetics. 2015 Apr;47(4):393-399. DOI: 10.1038/ng.3239. Epub 2015 Mar 9
  11. 11. Westenbroek RE, Merrick DK, Catterall WA. Differential subcellular localization of the RI and RII Na+ channel subtypes in central neurons. Neuron. 1989 Dec;3(6):695-704
  12. 12. Gong B, Rhodes KJ, Bekele-Arcuri Z, Trimmer JS. Type I and type II Na(+) channel alpha-subunit polypeptides exhibit distinct spatial and temporal patterning, and association with auxiliary subunits in rat brain. The Journal of Comparative Neurology. 1999 Sep;412(2):342-352
  13. 13. Meng H, Xu HQ, Yu L, Lin GW, He N, Su T, et al. The SCN1A mutation database: Updating information and analysis of the relationships among genotype, functional alteration, and phenotype. Human Mutation. 2015 Jun;36(6):573-580. DOI: 10.1002/humu.22782. Epub 2015 Apr 13
  14. 14. Escayg A, MacDonald BT, Meisler MH, Baulac S, Huberfeld G, An-Gourfinkel I, Malafosse A. Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nature Genetics. 2000;24:343-345
  15. 15. Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. American Journal of Human Genetics. 2001 Jun;68(6):1327-1332. Epub 2001 May 15
  16. 16. Weller CM, Pelzer N, de Vries B, López MA, De Fàbregues O, Pascual J, et al. Two novel SCN1A mutations identified in families with familial hemiplegic migraine. Cephalalgia. 2014 Nov;34(13):1062-1069. DOI: 10.1177/0333102414529195
  17. 17. Cheah CS, Yu FH, Westenbroek RE, Kalume FK, Oakley JC, Potter GB, et al. Specific deletion of NaV1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome. Proceedings of the National Academy of Sciences of the United States of America. 2012 Sep;109(36):14646-14651. DOI: 10.1073/pnas.1211591109. Epub 2012 Aug 20
  18. 18. Miller IO, Sotero de Menezes MA. SCN1A-related seizure disorders. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, Editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. 2007 Nov 29 [Updated 2014 May 15]
  19. 19. Wu YW, Sullivan J, McDaniel SS, Meisler MH, Walsh EM, Li SX, Kuzniewicz MW. Incidence of Dravet Syndrome in a US Population. Pediatrics. 2015 Nov;136(5):e1310-e1315. DOI: 10.1542/peds.2015-1807. Epub 2015 Oct 5
  20. 20. Gataullina S, Dulac O. From genotype to phenotype in Dravet disease. Seizure. 2017 Jan;44:58-64. DOI: 10.1016/j.seizure.2016.10.014. Epub 2016 Oct 21. Review
  21. 21. Dravet C. Dravet syndrome history. Developmental Medicine and Child Neurology. 2011 Apr;53(Suppl 2):1-6. DOI: 10.1111/j.1469-8749.2011.03964.x
  22. 22. Dravet C, Oguni H. Dravet syndrome (severe myoclonic epilepsy in infancy). Handbook of Clinical Neurology. 2013;111:627-633. DOI: 10.1016/B978-0-444-52891-9.00065-8
  23. 23. Ishii A, Watkins JC, Chen D, Hirose S, Hammer MF. Clinical implications of SCN1A missense and truncation variants in a large Japanese cohort with Dravet syndrome. Epilepsia. 2017 Feb;58(2):282-290. DOI: 10.1111/epi.13639. Epub 2016 Dec 24
  24. 24. Bechi G, Scalmani P, Schiavon E, Rusconi R, Franceschetti S, Mantegazza M. Pure haploinsufficiency for Dravet syndrome Na(V)1.1 (SCN1A) sodium channel truncating mutations. Epilepsia. 2012 Jan;53(1):87-100. DOI: 10.1111/j.1528-1167.2011.03346.x. Epub 2011 Dec 9
  25. 25. Kamiya K, Kaneda M, Sugawara T, Mazaki E, Okamura N, Montal M, et al. A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline. The Journal of Neuroscience. 2004;24:2690-2698
  26. 26. McArdle EJ, Kunic JD, George AL Jr. Novel SCN1A frameshift mutation with absence of truncated Nav1.1 protein in severe myoclonicepilepsy of infancy. American Journal of Medical Genetics. Part A. 2008 Sep;146A(18):2421-2423. DOI: 10.1002/ajmg.a.32448
  27. 27. Marini C, Scheffer IE, Nabbout R, Suls A, De Jonghe P, Zara F, Guerrini R. The genetics of Dravet syndrome. Epilepsia. 2011 Apr;52(Suppl 2):24-29. DOI: 10.1111/j.1528-1167.2011.02997.x
  28. 28. Hilber K, Sandtner W, Kudlacek O, Glaaser IW, Weisz E, Kyle JW, et al. The selectivity filter of the voltage-gated sodium channel is involved in channel activation. The Journal of Biological Chemistry. 2001 Jul;276(30):27831-27839. Epub 2001 May 29
  29. 29. Ohno Y, Ishihara S, Mashimo T, Sofue N, Shimizu S, Imaoku T, et al. Scn1a missense mutation causes limbic hyperexcitability and vulnerability to experimental febrile seizures. Neurobiology of Disease. 2011 Feb;41(2):261-269. DOI: 10.1016/j.nbd.2010.09.013. Epub 2010 Sep 25
  30. 30. Mashimo T, Ohmori I, Ouchida M, Ohno Y, Tsurumi T, Miki T, et al. A missense mutation of the gene encoding voltage-dependent sodium channel (Nav1.1) confers susceptibility to febrile seizures in rats. The Journal of Neuroscience. 2010 Apr;30(16):5744-5753. DOI: 10.1523/JNEUROSCI.3360-09.2010
  31. 31. Meadows L, Malhotra JD, Stetzer A, Isom LL, Ragsdale DS. The intracellular segment of the sodium channel beta 1 subunit is required for its efficient association with the channel α subunit. Journal of Neurochemistry. 2001;76(6):1871-1878
  32. 32. Yamagishi T, Li RA, Hsu K, Marbán E, Tomaselli GF. Molecular architecture of the voltage-dependent Na channel: Functional evidence for alpha helices in the pore. The Journal of General Physiology. 2001 Aug;118(2):171-182
  33. 33. Mantegazza M, Catterall WA. Voltage-gated Na+ channels: Structure, function, and pathophysiology. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, Editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th ed. Bethesda (MD): National Center for Biotechnology Information (US); 2012
  34. 34. Tsukamoto T, Chiba Y, Wakamori M, Yamada T, Tsunogae S, Cho Y, et al. Differential binding of tetrodotoxin and its derivatives to voltage-sensitive sodium channel subtypes (Nav 1.1 to Nav 1.7). British Journal of Pharmacology. 2017;174(21):3881-3892. DOI: 10.1111/bph.13985. Epub 2017 Sep 20
  35. 35. Onwuli DO, Beltran-Alvarez P. An update on transcriptional and post-translational regulation of brain voltage-gated sodium channels. Amino Acids. 2016 Mar;48(3):641-651. DOI: 10.1007/s00726-015-2122-y. Epub 2015 Oct 27
  36. 36. Patel RR, Barbosa C, Xiao Y, Cummins TR. Human Nav1.6 channels generate larger resurgent currents than human Nav1.1 channels, but the Navbeta4 peptide does not protect either isoform from use-dependent reduction. PLoS One. 2015 Jul;10(7):e0133485. DOI: 10.1371/journal.pone.0133485. eCollection 2015
  37. 37. Kaneko Y, Watanabe S. Expression of Nav1.1 in rat retinal AII amacrine cells. Neuroscience Letters. 2007 Sep;424(2):83-88. Epub 2007 Aug 1
  38. 38. Mistry AM, Thompson CH, Miller AR, Vanoye CG, George AL Jr, Kearney JA. Strain- and age-dependent hippocampal neuron sodium currents correlate with epilepsy severity in Dravet syndrome mice. Neurobiology of Disease. 2014 May;65:1-11. DOI: 10.1016/j.nbd.2014.01.006. Epub 2014 Jan 14
  39. 39. Ogiwara I, Miyamoto H, Morita N, Atapour N, Mazaki E, Inoue I, et al. Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: A circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation. The Journal of Neuroscience. 2007 May;27(22):5903-5914
  40. 40. De Stasi AM, Farisello P, Marcon I, Cavallari S, Forli A, Vecchia D, et al. Unaltered network activity and Interneuronal firing during spontaneous cortical dynamics in vivo in a mouse model of severe myoclonic epilepsy of infancy. Cerebral Cortex. 2016 Apr;26(4):1778-1794. DOI: 10.1093/cercor/bhw002. Epub 2016 Jan 26
  41. 41. Tang B, Dutt K, Papale L, Rusconi R, Shankar A, Hunter J, et al. A BAC transgenic mouse model reveals neuron subtype-specific effects of a generalized epilepsy with febrile seizures plus (GEFS+) mutation. Neurobiology of Disease. 2009 Jul;35(1):91-102. DOI: 10.1016/j.nbd.2009.04.007. Epub 2009 May 3
  42. 42. Isaacson JS, Scanziani M. How inhibition shapes cortical activity. Neuron. 2011 Oct;72(2):231-243. DOI: 10.1016/j.neuron.2011.09.027
  43. 43. Markram H, Toledo-Rodriguez M, Wang Y, Gupta A, Silberberg G, Wu C. Interneurons of the neocortical inhibitory system. Nature Reviews. Neuroscience. 2004 Oct;5(10):793-807
  44. 44. Hunt RF, Baraban SC. Interneuron transplantation as a treatment for epilepsy. Cold Spring Harbor Perspectives in Medicine. 2015 Dec;5(12):pii: a022376
  45. 45. Shetty AK, Upadhya D. GABA-ergic cell therapy for epilepsy: Advances, limitations and challenges. Neuroscience and Biobehavioral Reviews. 2016 Mar;62:35-47. DOI: 10.1016/j.neubiorev.2015.12.014
  46. 46. DeRosa BA, Belle KC, Thomas BJ, Cukier HN, Pericak-Vance MA, Vance JM, Dykxhoorn DM. hVGAT-mCherry:A novel molecular tool for analysis of GABAergic neurons derived from human pluripotent stem cells. Molecular and Cellular Neurosciences. 2015 Sep;68:244-257. DOI: 10.1016/j.mcn.2015.08.007
  47. 47. Bezaire MJ, Soltesz I. Quantitative assessment of CA1 local circuits: Knowledge base for interneuron-pyramidal cell connectivity. Hippocampus. 2013 Sep;23(9):751-785. DOI: 10.1002/hipo.22141. Epub 2013 Jul 10
  48. 48. Baude A, Bleasdale C, Dalezios Y, Somogyi P, Klausberger T. Immunoreactivity for the GABAA receptor alpha1 subunit, somatostatin and Connexin 36 distinguishes axoaxonic, basket, and bistratified interneurons of the rat hippocampus. Cerebral Cortex. 2007 Sep;17(9):2094-2107. Epub 2006 Nov 22
  49. 49. Pawelzik H, Hughes DI, Thomson AM. Modulation of inhibitory autapses and synapses on rat CA1 interneurones by GABA(A) receptor ligands. The Journal of Physiology. 2003 Feb;546(Pt 3):701-716
  50. 50. Somogyi P, Nunzi MG, Gorio A, Smith AD. A new type of specific interneuron in the monkey hippocampus forming synapses exclusively with the axon initial segments of pyramidal cells. Brain Research. 1983 Jan;259(1):137-142
  51. 51. Tian C, Wang K, Ke W, Guo H, Shu Y. Molecular identity of axonal sodium channels in human cortical pyramidal cells. Frontiers in Cellular Neuroscience. 2014 Sep;8:297. DOI: 10.3389/fncel.2014.00297. eCollection 2014
  52. 52. Sugino K, Hempel CM, Miller MN, Hattox AM, Shapiro P, Wu C, et al. Molecular taxonomy of major neuronal classes in the adult mouse forebrain. Nature Neuroscience. 2006 Jan;9(1):99-107. Epub 2005 Dec 20
  53. 53. Hu H, Jonas P. A supercritical density of Na(+) channels ensures fast signaling in GABAergic interneuron axons. Nature Neuroscience. 2014 May;17(5):686-693. DOI: 10.1038/nn.3678. Epub 2014 Mar 23
  54. 54. Li T, Tian C, Scalmani P, Frassoni C, Mantegazza M, Wang Y, et al. Action potential initiation in neocortical inhibitory interneurons. PLoS Biology. 2014;12(9):e1001944. DOI: 10.1371/journal.pbio.1001944. eCollection 2014 Sep
  55. 55. Grubb MS, Burrone J. Activity-dependent relocation of the axon initial segment fine-tunes neuronal excitability. Nature. 2010 Jun;465(7301):1070-1074. DOI: 10.1038/nature09160. Epub 2010 Jun 13
  56. 56. Grubb MS, Shu Y, Kuba H, Rasband MN, Wimmer VC, Bender KJ. Short- and long-term plasticity at the axon initial segment. The Journal of Neuroscience. 2011 Nov;31(45):16049-16055. DOI: 10.1523/JNEUROSCI.4064-11.2011
  57. 57. Hu W, Tian C, Li T, Yang M, Hou H, Shu Y. Distinct contributions of Na(v)1.6 and Na(v)1.2 in action potential initiation and backpropagation. Nature Neuroscience. 2009 Aug;12(8):996-1002. DOI: 10.1038/nn.2359. Epub 2009 Jul 26
  58. 58. Lorincz A, Nusser Z. Cell-type-dependent molecular composition of the axon initial segment. The Journal of Neuroscience. 2008 Dec;28(53):14329-14340. DOI: 10.1523/JNEUROSCI.4833-08.2008
  59. 59. Rush AM, Dib-Hajj SD, Waxman SG. Electrophysiological properties of two axonal sodium channels, Nav1.2 and Nav1.6, expressed in mouse spinal sensory neurones. The Journal of Physiology. 2005 May;564(Pt 3):803-815. Epub 2005 Mar 10
  60. 60. Spampanato J, Escayg A, Meisler MH, Goldin AL. Functional effects of two voltage-gated sodium channel mutations that cause generalized epilepsy with febrile seizures plus type 2. The Journal of Neuroscience. 2001 Oct;21(19):7481-7490
  61. 61. Laezza F, Lampert A, Kozel MA, Gerber BR, Rush AM, Nerbonne JM, et al. FGF14 N-terminal splice variants differentially modulate Nav1.2 and Nav1.6-encoded sodiumchannels. Molecular and Cellular Neurosciences. 2009 Oct;42(2):90-101. DOI: 10.1016/j.mcn.2009.05.007. Epub 2009 May 22
  62. 62. Alshammari TK, Alshammari MA, Nenov MN, Hoxha E, Cambiaghi M, Marcinno A, et al. Genetic deletion of fibroblast growth factor 14 recapitulates phenotypic alterations underlying cognitive impairment associated with schizophrenia. Translational Psychiatry. 2016 May;6:e806. doi: 10.1038/tp.2016.66
  63. 63. Goetz R, Dover K, Laezza F, Shtraizent N, Huang X, Tchetchik D, et al. Crystal structure of a fibroblast growth factor homologous factor (FHF) defines a conserved surface on FHFs for binding and modulation of voltage-gated sodium channels. The Journal of Biological Chemistry. 2009;284(26):17883-17896. DOI: 10.1074/jbc.M109.001842. Epub 2009 Apr 30
  64. 64. Shavkunov A1, Panova N, Prasai A, Veselenak R, Bourne N, Stoilova-McPhie S, Laezza F. Bioluminescence methodology for the detection of protein-protein interactions within the voltage-gated sodium channel macromolecular complex. ASSAY and Drug Development Technologies. 2012 Apr;10(2):148-60. doi: 10.1089/adt.2011.413. Epub 2012 Feb 24
  65. 65. Jones SL, Svitkina TM. Axon initial segment cytoskeleton: Architecture, development, and role in neuron polarity. Neural Plasticity. 2016;2016:6808293. DOI: 10.1155/2016/6808293. Epub 2016 Jul 17
  66. 66. Brackenbury WJ, Calhoun JD, Chen C, Miyazaki H, Nukina N, Oyama F, et al. Functional reciprocity between Na+ channel Nav1.6 and beta1 subunits in the coordinated regulation of excitability and neurite outgrowth. Proceedings of the National Academy of Sciences of the United States of America. 2010 Feb;107(5):2283-2288. DOI: 10.1073/pnas.0909434107. Epub 2010 Jan 19
  67. 67. Kuba H, Oichi Y, Ohmori H. Presynaptic activity regulates Na(+) channel distribution at the axon initial segment. Nature. 2010 Jun;465(7301):1075-1078. DOI: 10.1038/nature09087. Epub 2010 Jun 13
  68. 68. Wefelmeyer W, Cattaert D, Burrone J. Activity-dependent mismatch between axo-axonic synapses and the axon initial segment controls neuronal output. Proceedings of the National Academy of Sciences of the United States of America. 2015 Aug;112(31):9757-9762. DOI: 10.1073/pnas.1502902112. Epub 2015 Jul 20
  69. 69. Höfflin F, Jack A, Riedel C, Mack-Bucher J, Roos J, Corcelli C, et al. Heterogeneity of the axon initial segment in interneurons and pyramidal cells of rodent visual cortex. Frontiers in Cellular Neuroscience. 2017 Nov;11:332. DOI: 10.3389/fncel.2017.00332. eCollection 2017
  70. 70. Inan M, Blázquez-Llorca L, Merchán-Pérez A, Anderson SA, DeFelipe J, Yuste R. Dense and overlapping innervation of pyramidal neurons by chandelier cells. The Journal of Neuroscience. 2013 Jan;33(5):1907-1914. DOI: 10.1523/JNEUROSCI.4049-12.2013
  71. 71. Cruz DA, Eggan SM, Lewis DA. Postnatal development of pre- and postsynaptic GABA markers at chandelier cell connections with pyramidal neurons in monkey prefrontal cortex. The Journal of Comparative Neurology. 2003 Oct;465(3):385-400
  72. 72. Hardwick C, French SJ, Southam E, Totterdell S. A comparison of possible markers for chandelier cartridges in rat medial prefrontal cortex and hippocampus. Brain Research. 2005 Jan;1031(2):238-244
  73. 73. Bloomfield C, French SJ, Jones DN, Reavill C, Southam E, Cilia J, Totterdell S. Chandelier cartridges in the prefrontal cortex are reduced in isolation reared rats. Synapse. 2008 Aug;62(8):628-631. DOI: 10.1002/syn.20521
  74. 74. Pierri JN, Chaudry AS, Woo TU, Lewis DA. Alterations in chandelier neuron axon terminals in the prefrontal cortex of schizophrenic subjects. The American Journal of Psychiatry. 1999 Nov;156(11):1709-1719
  75. 75. Guerrini R, Dravet C, Genton P, Belmonte A, Kaminska A, Dulac O. Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia. 1998 May;39(5):508-512
  76. 76. Shi XY, Tomonoh Y, Wang WZ, Ishii A, Higurashi N, Kurahashi H, et al. Efficacy of antiepileptic drugs for the treatment of Dravet syndrome with different genotypes. Brain & Development. 2016 Jan;38(1):40-46. DOI: 10.1016/j.braindev.2015.06.008. Epub 2015 Jul 13
  77. 77. Hirose S, Scheffer IE, Marini C, De Jonghe P, Andermann E, Goldman AM, et al. SCN1A testing for epilepsy: Application in clinical practice. Epilepsia. 2013 May;54(5):946-952. DOI: 10.1111/epi.12168. Epub 2013 Apr 15
  78. 78. Hattori J, Ouchida M, Ono J, Miyake S, Maniwa S, Mimaki N, et al. A screening test for the prediction of Dravet syndrome before one year of age. Epilepsia. 2008 Apr;49(4):626-633. Epub 2007 Dec 11
  79. 79. Stenhouse SA, Ellis R, Zuberi S. SCN1A genetic test for Dravet Syndrome (severe myoclonic epilepsy of infancy and its clinical subtypes) for use in the diagnosis, prognosis, treatment and management of Dravet syndrome. PLOS Currents. 2013;5. pii: ecurrents.eogt.c553b83d745dd79bfb61eaf35e522b0b. DOI: 10.1371/currents.eogt.c553b83d745dd79bfb61eaf35e522b0b
  80. 80. Connolly MB. Dravet syndrome: Diagnosis and long-term course. The Canadian Journal of Neurological Sciences. 2016 Jun;43(Suppl 3):S3-S8. DOI: 10.1017/cjn.2016.243
  81. 81. Snoeijen-Schouwenaars FM, Veendrick MJ, an Mierlo P, van Erp G, de Louw AJ, Kleine BU, et al. Carbamazepine and oxcarbazepine in adult patients with Dravet syndrome: Friend or foe? Seizure 2015 Jul;29:114-118. DOI: 10.1016/j.seizure.2015.03.010. Epub 2015 Apr 13
  82. 82. Lotte J, Haberlandt E, Neubauer B, Staudt M, Kluger GJ. Bromide in patients with SCN1A-mutations manifesting as Dravet syndrome. Neuropediatrics. 2012 Feb;43(1):17-21. DOI: 10.1055/s-0032-1307454. Epub 2012 Mar 19
  83. 83. Iannetti P, Parisi P, Spalice A, Ruggieri M, Zara F. Addition of verapamil in the treatment of severe myoclonic epilepsy in infancy. Epilepsy Research. 2009 Jul;85(1):89-95. DOI: 10.1016/j.eplepsyres.2009.02.014. Epub 2009 Mar 20
  84. 84. Striano P, Coppola A, Pezzella M, Ciampa C, Specchio N, Ragona F, et al. An open-label trial of levetiracetam in severe myoclonic epilepsy of infancy. Neurology 2007 Jul;69(3):250-254
  85. 85. De Liso P, Chemaly N, Laschet J, Barnerias C, Hully M, Leunen D, et al. Patients with Dravet syndrome in the era of stiripentol: A French cohort cross-sectional study. Epilepsy Research 2016 Sep;125:42-46. doi: 10.1016/j.eplepsyres.2016.05.012. Epub 2016 May 28
  86. 86. Balestrini S, Sisodiya SM. Audit of use of stiripentol in adults with Dravet syndrome. Acta Neurologica Scandinavica. 2017 Jan;135(1):73-79. DOI: 10.1111/ane.12611. Epub 2016 May 27
  87. 87. Fulton SP, Van Poppel K, McGregor AL, Mudigoudar B, Wheless JW. Vagus nerve stimulation in intractable epilepsy associated with SCN1A gene abnormalities. Journal of Child Neurology. 2017 Apr;32(5):494-498. DOI: 10.1177/0883073816687221. Epub 2017 Jan 12
  88. 88. Baraban SC, Dinday MT, Hortopan GA. Drug screening in Scn1a zebrafish mutant identifies clemizole as a potential Dravet syndrome treatment. Nature Communications. 2013;4:2410. DOI: 10.1038/ncomms3410
  89. 89. Ohmori I, Kawakami N, Liu S, Wang H, Miyazaki I, Asanuma M, et al. Methylphenidate improves learning impairments and hyperthermia-induced seizures caused by an Scn1a mutation. Epilepsia. 2014 Oct;55(10):1558-1567. DOI: 10.1111/epi.12750
  90. 90. Hayashi K, Ueshima S, Ouchida M, Mashimo T, Nishiki T, Sendo T, et al. Therapy for hyperthermia-induced seizures in Scn1a mutant rats. Epilepsia. 2011 May;52(5):1010-1017. DOI: 10.1111/j.1528-1167.2011.03046.x
  91. 91. Kwan P, Sills GJ, Brodie MJ. The mechanisms of action of commonly used antiepileptic drugs. Pharmacology & Therapeutics. 2001 Apr;90(1):21-34
  92. 92. Ceulemans B, Boel M, Claes L, Dom L, Willekens H, Thiry P, Lagae L. Severe myoclonic epilepsy in infancy: Toward an optimal treatment. Journal of Child Neurology. 2004 Jul;19(7):516-521
  93. 93. Trojnar MK, Wojtal K, Trojnar MP, Czuczwar SJ. Stiripentol. A novel antiepileptic drug. Pharmacological Reports. 2005 Mar-Apr;57(2):154-160
  94. 94. Ryan M, Baumann RJ. Use and monitoring of bromides in epilepsy treatment. Pediatric Neurology. 1999 Aug;21(2):523-528
  95. 95. Kwan P, Brodie MJ. Early identification of refractory epilepsy. The New England Journal of Medicine. 2000 Feb;342(5):314-319
  96. 96. Wang GX, Wang DW, Liu Y, Ma YH. Intractable epilepsy and the P-glycoprotein hypothesis. The International Journal of Neuroscience. 2016;126(5):385-392. DOI: 10.3109/00207454.2015.1038710. Epub 2015 Jul 2
  97. 97. Kwan P, Poon WS, Ng HK, Kang DE, Wong V, Ng PW, Lui CH, Sin NC, Wong KS, Baum L. Multidrug resistance in epilepsy and polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, and SCN3A: Correlation among phenotype, genotype, and mRNA expression. Pharmacogenetics and Genomics. 2008 Nov;18(11):989-998. DOI: 10.1097/FPC.0b013e3283117d67
  98. 98. Lv N, Qu J, Long H, Zhou L, Cao Y, Long L, Liu Z, Xiao B. Association study between polymorphisms in the CACNA1A, CACNA1C, and CACNA1H genes and drug-resistant epilepsy in the Chinese Han population. Seizure. 2015 Aug;30:64-69. DOI: 10.1016/j.seizure.2015.05.013. Epub 2015 May 28
  99. 99. Huberfeld G, Wittner L, Clemenceau S, Baulac M, Kaila K, Miles R, Rivera C. Perturbed chloride homeostasis and GABAergic signaling in human temporal lobe epilepsy. The Journal of Neuroscience. 2007 Sep;27(37):9866-9873
  100. 100. Lachos J, Zattoni M, Wieser HG, Fritschy JM, Langmann T, Schmitz G, et al. Characterization of the gene expression profile of human hippocampus in mesial temporal lobe epilepsy with hippocampal sclerosis. Epilepsy Research and Treatment. 2011;2011:758407. DOI: 10.1155/2011/758407. Epub 2011 Mar 6

Written By

Tian Li

Submitted: 28 November 2017 Reviewed: 12 March 2018 Published: 10 October 2018