Expecting the Unexpected: Lack of in Vivo Network Defects in an Scn1a Model of Dravet Syndrome

Abstract

CommentaryDravet syndrome (DS) is a severe pediatric epileptic encephalopathy with disease onset in the first year of life. Patients have normal presentation before seizure onset and then experience frequent seizures, ataxia, cognitive deficits, and a high risk of sudden unexpected death in epilepsy (1). The majority of DS cases are caused by de novo loss-of-function mutations in SCN1A, encoding the voltage-gated sodium channel Na v 1.1, resulting in haploinsufficiency (2-4).Early studies in Scn1a −/+ mice showed selective reductions in excitability and sodium current density in hippocampal interneurons, with pyramidal neurons unaffected, at postnatal day (P)13 to 14 (4). These data pointed to selective impairment of GABAergic interneurons in DS, leading to disinhibition and epilepsy. Subsequent work with cell type specific Scn1a deletions to study the roles of inhibitory interneuron subtypes supported this hypothesis (5-7). However, work in DS patientderived induced pluripotent stem cell neurons and in DS mice during the time of disease onset (P21-24) suggested a role for increased pyramidal neuron excitability in pathogenesis (8, 9). Disease onset and severity are correlated with increased Scn1a−/+ hippocampal pyramidal neuron excitability compared to wildtype (WT), while interneuron excitability is decreased before and after disease onset (9). Regardless of contributions from other neuron types, interneurons are involved in various network oscillations, suggesting their dysfunction should translate to dramatic network effects in vivo (10).In their article in Cerebral Cortex, De Stasi et al. set out to address the in vivo network impacts of SCN1A-linked DS in mice. In vivo local field potential (LFP) and multiunit activity (MUA) recordings were performed in the somatosensory cortex of P16 to 18 WT and Scn1a −/+ mice. Importantly, Scn1a−/+ mice in this age range have not yet begun to exhibit seizures and have been shown using whole cell patch clamp in acute brain slices to have hypoexcitability of parvalbumin positive (PV+) and somatostatin positive (SOM+) interneurons of the cortex and hippocampus (4, 5, 9). Here, under urethane anesthesia, De Stasi et al. demonstrated that the only differences in the LFP power spectrum between genotypes are modest reductions in the δ (2-4 Hz) and θ (4-8 Hz) frequency bands when recording from superficial cortical layers. In deep layer recordings, no differences were found between genotypes in the LFP power spectrum at any frequency. To test if the subtle differences were due to anesthesia, experiments were repeated in awake animals; however, no differences were found in the LFP power spectrum at any frequency. In addition, no differences in neuronal spiking were detected in the MUA signal Severe myoclonic epilepsy of infancy (SMEI) is associated with loss of function of the SCN1A gene encoding the NaV1.1 sodium channel isoform. Previous studies in Scn1a −/+ mice during the pre-epileptic period reported selective reduction in interneuron excitability and proposed this as the m...

Early-life febrile seizures worsen adult phenotypes in Scn1a mutants

“…It has also been shown that alterations in interneuronal firing seen in Scn1a +/− DS mice do not alter intrinsic network excitability in vivo (De Stasi et al 2016). According to Hull and Isom (2016), there might be other factors such as pyramidal neuron hypere xcitability that alter the network dynamics during a seizure, and pyramidal neuron function has been shown to be altered in neurons derived from induced pluripotent stem cells from Dravet patients (Liu et al 2013). For these reasons, we investigated the firing properties of pyramidal neurons in the current study, and we found increased excitability in CA3 pyramidal neurons of mutant mice that had undergone A/PFE.…”

Sexually Divergent Mortality and Partial Phenotypic Rescue After Gene Therapy in a Mouse Model of Dravet Syndrome

“…Voltage-gated sodium channels, such as NaV1.1, are heterotrimeric protein complexes consisting of a single large pore-forming a subunit in combination with two much smaller b subunits. 20 The noncovalently linked b1 subunit has been shown to modulate the function of the a subunits by enhancing ion flow through a subunits, and by promoting the trafficking of the a subunits from an intracellular pool to the cell surface. 21 We hypothesized that overexpression of NaVb1 would facilitate the activity of residual sodium channel subunits in Scn1a +/mice and mitigate the DS phenotype.…”