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Reduced dendritic arborization and hyperexcitability of pyramidal neurons in a Scn1b-based model of Dravet syndrome

Christopher A. Reid, Bryan Leaw, Kay L. Richards, Robert Richardson, Verena Wimmer, Christiaan Yu, Elisa L. Hill-Yardin, Holger Lerche, Ingrid E. Scheffer, Samuel F. Berkovic, Steven Petrou
DOI: http://dx.doi.org/10.1093/brain/awu077 1701-1715 First published online: 17 April 2014


Epileptic encephalopathies, including Dravet syndrome, are severe treatment-resistant epilepsies with developmental regression. We examined a mouse model based on a human β1 sodium channel subunit (Scn1b) mutation. Homozygous mutant mice shared phenotypic features and pharmaco-sensitivity with Dravet syndrome. Patch-clamp analysis showed that mutant subicular and layer 2/3 pyramidal neurons had increased action potential firing rates, presumably as a consequence of their increased input resistance. These changes were not seen in L5 or CA1 pyramidal neurons. This raised the concept of a regional seizure mechanism that was supported by data showing increased spontaneous synaptic activity in the subiculum but not CA1. Importantly, no changes in firing or synaptic properties of gamma-aminobutyric acidergic interneurons from mutant mice were observed, which is in contrast with Scn1a-based models of Dravet syndrome. Morphological analysis of subicular pyramidal neurons revealed reduced dendritic arborization. The antiepileptic drug retigabine, a K+ channel opener that reduces input resistance, dampened action potential firing and protected mutant mice from thermal seizures. These results suggest a novel mechanism of disease genesis in genetic epilepsy and demonstrate an effective mechanism-based treatment of the disease.

  • epileptic encephalopathy
  • Dravet syndrome
  • sodium channel
  • beta1 subunit
  • action potentials
  • Abbreviations
    gamma-aminobutyric acid
    postsynaptic current
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