Publication in detail

Brain. 2014 Jun;137(Pt 6):1701-15. doi: 10.1093/brain/awu077.

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

Reid, CA; Leaw, B; Richards, KL; Richardson, R; Wimmer, V; Yu, C; Hill-Yardin, EL; Lerche, H; Scheffer, IE; Berkovic, SR; Petrou, S

Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville, 3010, Australia. Department of Neurology and Epileptology, Hertie Institute of Clinical Brain Research, University of Tübingen, Germany. Neurological Clinic and

Abstract:
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.

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