Dravet syndrome: a sodium channel interneuronopathy
Introduction
Voltage-gated sodium (NaV) channels initiate action potentials in neurons and other excitable cells [1]. They are composed of a large central pore-forming α subunit in complex with one or two auxiliary β subunits [2]. In response to depolarizing stimuli, brain NaV channels rapidly activate, open, and then inactivate with 1–2 ms [1, 2]. A further slow inactivation process is engaged by long trains of stimuli or prolonged depolarizations in the range of 100 ms [3]. The kinetics and voltage dependence of sodium channel activation and inactivation strongly influence the threshold for action potential firing and the initiation, firing frequency, and durations of trains of action potentials [3]. Because information is encoded in the frequency and pattern of trains of action potentials, sodium channels play critical roles in information processing in neural circuits as well as in information transmission throughout the brain.
Section snippets
Dravet syndrome
Dravet syndrome is a devastating childhood epilepsy disorder with a high incidence of premature death plus co-morbidities of developmental delay, severe cognitive impairment, ataxia, circadian rhythm disorder, impaired sleep quality, and autistic-like social interaction deficits [4]. It is primarily caused by heterozygous loss-of-function mutations in the SCN1A gene that encodes the brain voltage-gated sodium channel type-1, termed NaV1.1 [4]. Approximately 80% of patients with a clinical
Mouse genetic models of epilepsy and premature death in Dravet syndrome
It is a paradox that loss-of-function mutations in a NaV channel cause epilepsy. Two mouse genetic models of Dravet syndrome based on different disease mutations both showed spontaneous seizures (Figure 1a). Surprisingly, these loss-of-function mutations have a specific effect to reduce the sodium currents and electrical excitability of GABAergic interneurons [6, 7], which would imbalance the ratio of excitation and inhibition in neural circuits throughout the brain and lead to general
Ataxia
The first co-morbidity to be analyzed in a mouse model of Dravet syndrome was ataxia. A mild ataxia phenotype was observed in digital video recordings [16]. Electrophysiological studies revealed a defect in action potential firing in cerebellar Purkinje neurons [16]. This defect is sufficient to cause ataxia, because deficits of similar magnitude in Purkinje cell function cause ataxia in other contexts (Table 1).
Circadian rhythm
Dravet syndrome children have a circadian rhythm defect, which prevents them from
Interneuron types
In the cerebral cortex, interneurons can be divided into three non-overlapping classes, recognizable by their expression of the marker proteins parvalbumin (PV), somatostatin (SST), and serotonin receptor 3a (5-HT3aR) [27]. PV interneurons make synapses on the cell bodies and axon initial segments of pyramidal neurons, where their fast-spiking discharges exert potent inhibition of action potential firing by their postsynaptic target [27]. SST interneurons make synapses on distal synapses of
Genetic background effects
Children with apparently complete loss-of-function mutations in NaV1.1 have different time course and severity of Dravet syndrome symptoms, implicating strong effects of genetic background in determining disease severity [22]. All of our studies cited above were carried out with NaV1.1 mutations expressed in homozygous C57BL/6J mice, which recapitulate all of the phenotypes of human Dravet syndrome [11, 25]. With this genetic background, all of the effects of these mutations are caused by
Current therapy
Current treatment of Dravet syndrome is not sufficient to prevent the storm of seizures and debilitating co-morbidities that are characteristic of this disease, even though combinations of antiepileptic drugs are used [5]. One standard treatment includes four antiepileptic drugs: valproate, clobazam, topiramate, and stiripentol [5]. The nontraditional antiepileptic drug leviteracetam is also frequently used as an add-on medication [37]. Unfortunately, even with these complex drug cocktails,
Conclusion
Studies of multiple mouse genetic models of Dravet syndrome all lead to the conclusion that the primary pathogenic event is loss of action firing in GABAergic interneurons. This loss of electrical excitability in GABAergic interneurons leads to an imbalance of excitation over inhibition in many neural circuits. This imbalance leads directly to the severe epilepsy, premature death, and many co-morbidities of Dravet syndrome. Genetic dissection of the phenotypes of Dravet syndrome indicates
Conflict of interest
The author declares no conflicts of interest.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Research on Dravet syndrome in the author's laboratory was supported by the National Institute of Neurological Disorders & Stroke of the National Institutes of Health (Research Grant R01 25470) and by a grant from the Simons Foundation.
References (47)
From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels
Neuron
(2000)- et al.
Sleep impairment and reduced interneuron excitability in a mouse model of Dravet syndrome
Neurobiol Dis
(2015) - et al.
The reticular nucleus revisited: intrinsic and network properties of a thalamic pacemaker
Prog Neurobiol
(2005) - et al.
Autism in Dravet syndrome: prevalence, features, and relationship to the clinical characteristics of epilepsy and mental retardation
Epilepsy Behav
(2011) - et al.
Mouse with NaV1.1 haploinsufficiency, a model for Dravet syndrome, exhibits lowered sociability and learning impairment
Neurobiol Dis
(2013) - et al.
Disynaptic inhibition between neocortical pyramidal cells mediated by Martinotti cells
Neuron
(2007) - et al.
Genetic background modulates impaired excitability of inhibitory neurons in a mouse model of Dravet syndrome
Neurobiol Dis
(2015) - et al.
Mapping genetic modifiers of survival in a mouse model of Dravet syndrome
Genes Brain Behav
(2014) Ionic Channels of Excitable Membranes
(2001)- et al.
Slow inactivation in voltage-gated sodium channels: molecular substrates and contributions to channelopathies
Cell Biochem Biophys
(2001)
The core Dravet syndrome phenotype
Epilepsia
The pharmacologic treatment of Dravet syndrome
Epilepsia
Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy
Nat Neurosci
NaV1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation
J Neurosci
Hippocampal hyperexcitability and specific epileptiform activity in a mouse model of Dravet syndrome
Epilepsia
Temperature- and age-dependent seizures in a mouse model of severe myoclonic epilepsy in infancy
Proc Natl Acad Sci U S A
Sudden unexpected death in a mouse model of Dravet syndrome
J Clin Invest
NaV1.1 channels and epilepsy
J Physiol
Dravet syndrome: insights from in vitro experimental models
Epilepsia
Correlations in timing of sodium channel expression, epilepsy, and sudden death in Dravet syndrome
Channels (Austin)
Specific deletion of NaV1.1 sodium channels in inhibitory interneurons causes seizures and premature death in a mouse model of Dravet syndrome
Proc Natl Acad Sci U S A
NaV1.1 haploinsufficiency in excitatory neurons ameliorates seizure-associated sudden death in a mouse model of Dravet syndrome
Hum Mol Genet
Reduced sodium current in Purkinje neurons from NaV1.1 mutant mice: implications for ataxia in severe myoclonic epilepsy in infancy
J Neurosci
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