Developmental progression of respiratory dysfunction in a mouse model of Dravet syndrome

TL;DR

This study shows that breathing problems appear early in Dravet syndrome and may predict sudden death, offering a potential biomarker and treatment target.

Contribution

The study identifies disordered breathing as an early biomarker of SUDEP in Dravet syndrome and shows Nav1.1 activation can rescue breathing deficits.

Findings

Scn1a+/– mice show impaired ventilatory responses to CO2/H+ and hypoxia before seizures.

Respiratory dysfunction severity correlates with mortality in Dravet syndrome.

Pharmacological Nav1.1 activation rescues RTN neuron activity deficits.

Abstract

Dravet syndrome (DS) is an early-onset epilepsy caused by loss-of-function mutations in the SCN1A gene, which encodes Nav1.1 channels that preferentially regulate activity of inhibitory neurons early in development. DS is associated with a high incidence of sudden unexpected death in epilepsy (SUDEP) by a mechanism that may involve respiratory failure. Evidence also shows that loss of Scn1a impaired activity of neurons in the retrotrapezoid nucleus (RTN) that regulate breathing in response to CO2/H+, suggesting breathing problems precede seizures and serve as a biomarker of SUDEP. Consistent with this, we showed that Scn1a+/– mice exhibited a blunted ventilatory response to CO2/H+ prior to overt seizure activity that worsened with disease progression. Later in development, some Scn1a+/– mice also showed a blunted ventilatory response to hypoxia. Importantly, the severity of respiratory problems correlated with mortality. We also found that pharmacological activation of Nav1.1 rescued activity deficits of RTN neurons in Scn1a+/– mice. We conclude that disordered breathing may be an early biomarker of SUDEP in DS, and at the cellular level, loss of Scn1a disrupts RTN neurons by mechanisms involving disinhibition and pharmacological activation of Nav1.1 to reestablish inhibitory control of RTN neurons rescues activity deficits.

Here, we identify a substrate that contributes to disordered breathing in Dravet syndrome and establish breathing problems as an biomarker of mortality in this disease.

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