Abstracts

Rationale: Dravet syndrome (DS) is a severe form of epilepsy that manifests in early childhood. DS is associated with frequent drug-resistant seizures, developmental problems, and sudden unexpected death. Around 80% of individuals with DS have a mutation in the Scn1a gene, which encodes the voltage-gated sodium channel Nav1.1. This channel is expressed primarily in inhibitory neurons and is known to play a role in determining the balance of excitation and inhibition in cortex. Scn1a is also highly expressed in the reticular nucleus of the thalamus (nRT), a GABAergic structure that projects to the thalamocortical relay nuclei and is known to play a role in the initiation and maintenance of different types of generalized seizures. Here we combined in vitro and in vivo electrophysiology, optogenetic and pharmacological manipulations, computational modeling, to interrogate the role of the nRT in DS seizures. Methods: In vitro whole-cell and extracellular LFP recordings; Cortical and thalamic unit and multi-unit recordings combined with optogenetics and pharmacology in freely behaving mice; Computational modeling; qPCR; Imaging; comparison of DS mouse and human EEG. Results: nRT cells in DS mice were found to have prolonged bursting activity (p<0.01) resulting from a reduced SK current (p<0.01). The thalamic microcircuit exhibited hyperactivity in vitro and generated abnormally long oscillatory bursting (p<0.01). In vivo, we observed frequent and atypical absence seizures in DS mice that had similar characteristics to those observed in human patients. These seizures could be treated by targeting the thalamus with either an SK channel agonist or optogenetic manipulations in freely behaving mice. Finally, a biophysical model of the nRT and dorsal thalamus demonstrated that changes in SK currents and not changes to sodium currents could drive the network excitability that we observed in the mouse model. Conclusions: These studies suggest that the reticular thalamus plays an important role in DS that is mediated by an unexpected change in potassium rather than sodium currents. Our findings indicate that the thalamic microcircuit and thalamic SK channels could be a target for the treatment of DS.  Funding: AES, Dravet Syndrome Foundation, Gladstone Institutes