Delayed maturation of GABAergic signaling in the Scn1a and Scn1b mouse models of Dravet Syndrome

Abstract

Dravet syndrome (DS) is a catastrophic developmental and epileptic encephalopathy characterized by severe, pharmacoresistant seizures and the highest risk of Sudden Unexpected Death in Epilepsy (SUDEP) of all epilepsy syndromes. Here, we investigated the time course of maturation of neuronal GABAergic signaling in the Scn1b −/− and Scn1a +/− mouse models of DS. We found that GABAergic signaling remains immature in both DS models, with a depolarized reversal potential for GABA A -evoked currents compared to wildtype in the third postnatal week. Treatment of Scn1b −/− mice with bumetanide resulted in a delay in SUDEP onset compared to controls in a subset of mice, without prevention of seizure activity or amelioration of failure to thrive. We propose that delayed maturation of GABAergic signaling may contribute to epileptogenesis in SCN1B - and SCN1A -linked DS. Thus, targeting the polarity of GABAergic signaling in brain may be an effective therapeutic strategy to reduce SUDEP risk in DS.

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

“…6D, F, 9C and Table 2B). This small reduction may be attributed to impaired activity of inhibitory neurons, alteration in the reversal potential of chloride (Yuan et al, 2019), or both.…”

Excitatory and inhibitory neuron defects in a mouse model of Scn1b‐linked EIEE52

“…The failure-to-thrive phenotype of Scn1b -/pups precluded the implantation of EEG electrodes. 28 Behavioral seizures were not observed in Scn1b Fl/Fl /Emx1-Cre or Scn1b Fl/Fl / Camk2a-Cre mice and all mice survived for more than 90 days. These data suggest a crucial role for PV + interneurons in Scn1b-linked seizures and SUDEP.…”

“…34 In other work, we reported that the time courses of maturation of neuronal GABAergic signaling in neocortical layer II/III and hippocampal CA1 or CA3 pyramidal cells are delayed in both the Scn1b −/− and Scn1a +/− mouse models of DEE, such that GABAergic signaling remains excitatory in these brain regions for significantly longer periods of development compared to WT. 28 This important point should be considered in the context of both DS and EIEE52 when discussing the effects of disinhibition, in that defects are not limited to impaired PV + neuron firing but also that inhibitory neurotransmission is further dampened by the impaired capacity of postsynaptic cells to receive these inputs as inhibitory. We found that the mean reversal potential for GABA in Scn1a +/− neurons was less depolarized than that of Scn1b −/− neurons over a similar developmental time range, again suggesting that these two DEE models exhibit ª 2020 The Authors.…”

“…Our laboratory previously measured, using the perforated patch technique, a depolarized reversal potential of synaptic Clcurrents in Scn1b -/mice relative to their WT littermates. 28 To ensure that this abnormal intracellular Clconcentration did not affect our synaptic recordings in this study, we used the wholecell recording technique with high intracellular Clto abolish any effects on the detected frequency of events. We compared the cumulative probability distributions of event amplitudes between genotypes and found that, following the 5-min equilibration period with the whole-cell internal solution, that they were not from statistically different distributions using the KS test ( Fig.…”

Scurrying to Understand Sudden Expected Death in Epilepsy: Insights From Animal Models

“…28,29 A delayed maturation of GABAergic signaling may contribute to epileptogenesis in this model. 30 Mice have a lower threshold for spreading depolarization, 31 and neurons derived from patients with Dravet syndrome show hyperexcitability, and cardiac myocytes show increased spontaneous contraction rates. 32,33 Abnormal sleep architecture but not total sleep duration probably due to an imbalance between excitatory and inhibitory neurons in the thalamocortical network.…”