Elsevier

Current Opinion in Physiology

Volume 2, April 2018, Pages 42-50
Current Opinion in Physiology

Dravet syndrome: a sodium channel interneuronopathy

https://doi.org/10.1016/j.cophys.2017.12.007Get rights and content

Highlights

  • Dravet syndrome results from heterozygous loss-of-function mutation of Nav1.1 channel.

  • Mouse genetic models recapitulate all aspects of the disease.

  • Epilepsy is caused by loss of action potential firing in GABAergic inhibitory neurons.

  • Co-morbidities also correlate with loss of excitability of inhibitory neurons.

  • Novel therapeutic approaches show promise for improved treatment.

Dravet syndrome is a devastating childhood epilepsy disorder with high incidence of premature death plus co-morbidities of ataxia, circadian rhythm disorder, impaired sleep quality, autistic-like social-interaction deficits and severe cognitive impairment. It is primarily caused by heterozygous loss-of-function mutations in the SCN1A gene that encodes brain voltage-gated sodium channel type-1, termed NaV1.1. Here I review experiments on mouse genetic models that implicate specific loss of sodium currents and action potential firing in GABAergic inhibitory interneurons as the fundamental cause of Dravet syndrome. The resulting imbalance of excitatory to inhibitory neurotransmission in neural circuits causes both epilepsy and co-morbidities. Promising therapeutic approaches involving atypical sodium channel blockers, novel drug combinations, and cannabidiol give hope for improved outcomes for Dravet syndrome patients.

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.

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