A Transient Developmental Window of Fast-Spiking Interneuron Dysfunction in a Mouse Model of Dravet Syndrome

Abstract

Dravet syndrome is a severe, childhood-onset epilepsy largely due to heterozygous loss-of-function mutation of the gene , which encodes the type 1 neuronal voltage-gated sodium (Na) channel α subunit Nav1.1. Prior studies in mouse models of Dravet syndrome ( mice) indicate that, in cerebral cortex, Nav1.1 is predominantly expressed in GABAergic interneurons, in particular in parvalbumin-positive fast-spiking basket cell interneurons (PVINs). This has led to a model of Dravet syndrome pathogenesis in which Nav1.1 mutation leads to preferential dysfunction of interneurons, decreased synaptic inhibition, hyperexcitability, and epilepsy. However, such studies have been implemented at early developmental time points. Here, we performed electrophysiological recordings in acute brain slices prepared from male and female mice as well as age-matched wild-type littermate controls and found that, later in development, the excitability of PVINs had normalized. Analysis of action potential waveforms indirectly suggests a reorganization of axonal Na channels in PVINs from mice, a finding supported by immunohistochemical data showing elongation of the axon initial segment. Our results imply that transient impairment of action potential generation by PVINs may contribute to the initial appearance of epilepsy, but is not the mechanism of ongoing, chronic epilepsy in Dravet syndrome. Dravet syndrome is characterized by normal early development, temperature-sensitive seizures in infancy, progression to treatment-resistant epilepsy, developmental delay, autism, and sudden unexplained death due to mutation in encoding the Na+ channel subunit Nav1.1. Prior work has revealed a preferential impact of Nav1.1 loss on the function of GABAergic inhibitory interneurons. However, such data derive exclusively from recordings of neurons in young mice. Here, we show that impaired action potential generation observed in parvalbumin-positive fast-spiking interneurons (PVINs) in+/- mice during early development has normalized by postnatal day 35. This work suggests that a transient impairment of PVINs contributes to epilepsy onset, but is not the mechanism of ongoing, chronic epilepsy in Dravet syndrome.

New insights into the early mechanisms of epileptogenesis in a zebrafish model of Dravet syndrome

“…Notably, a study that performed electrophysiological recordings on acute brain slices from Scn1a ± mice found that, at later developmental stages, parvalbumin‐positive fast‐spiking basket cell interneuron excitability normalized. The results of this study implied that impairing action potential generation by parvalbumin‐positive fast‐spiking basket cell interneurons contribute to the initial epilepsy phenotype but may not be the sole mechanism that drives later, chronic epilepsy in DS . It is equally important, however, to consider that the variable severity and expressivity of the murine Scn1a ± epilepsy phenotype is highly strain dependent .…”

“…The results of this study implied that impairing action potential generation by parvalbumin-positive fast-spiking basket cell interneurons contribute to the initial epilepsy phenotype but may not be the sole mechanism that drives later, chronic epilepsy in DS. 47 It is equally important, however, to consider that the variable severity and expressivity of the murine Scn1a ± epilepsy phenotype is highly strain dependent. 48,49 Therefore, it will be interesting to explore whether stabilization of interneuron activity can be recapitulated in the zebrafish scn1lab wt/mut .…”

Scn8a Antisense Oligonucleotide Is Protective in Mouse Models of SCN8A Encephalopathy and Dravet Syndrome

“…This extended period of protection after a single treatment suggests that ASO administration during a critical period of postnatal development might give long‐term seizure control in Dravet patients. A transient developmental window of interneuron dysfunction has been described in Dravet mice . Expansion of future testing of the Scn8a ASO to other seizure models will be of great interest.…”

“…A transient developmental window of interneuron dysfunction has been described in Dravet mice. 34 Expansion of future testing of the Scn8a ASO to other seizure models will be of great interest.…”

Early hippocampal hyperexcitability followed by disinhibition in a mouse model of Dravet syndrome

“…Despite extensive studies of these models, the neuronal basis of Dravet and the mechanisms underlying the different stages are still debated, with evidence in favor of reduced function of inhibitory neurons, or enhanced function of excitatory neurons. In support of the "inhibitory neuron" hypothesis, electrophysiological studies demonstrated impaired firing of multiple types of inhibitory neurons during the worsening stage, with no apparent change in the excitability of excitatory neurons (De Stasi et al, 2016;Favero et al, 2018;Goff and Goldberg, 2019;Han et al, 2012;Ogiwara et al, 2007;Rubinstein et al, 2015bRubinstein et al, , 2015aTai et al, 2014;Tsai et al, 2015). Moreover, selective deletion of Scn1a in inhibitory neurons was sufficient to cause seizures and premature mortality Kalume et al, 2013;Kuo et al, 2019;Ogiwara et al, 2013;Rubinstein et al, 2015a).…”