Augmented Reticular Thalamic Bursting and Seizures in Scn1a-Dravet Syndrome

Stefanie Ritter-Makinson; Alexandra Clemente-Perez; Bryan Higashikubo; Frances S Cho; Stephanie S Holden; Eric Bennett; Ana Chkhaidze; Oscar H J Eelkman Rooda; Marie-Coralie Cornet; Freek E Hoebeek; Kazuhiro Yamakawa; Maria Roberta Cilio; Bruno Delord; Jeanne T Paz

doi:10.1016/j.celrep.2018.12.018

Augmented Reticular Thalamic Bursting and Seizures in Scn1a-Dravet Syndrome

Cell Rep. 2019 Jan 2;26(1):54-64.e6. doi: 10.1016/j.celrep.2018.12.018.

Authors

Affiliations

¹ Gladstone Institute of Neurological Disease, San Francisco, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
² Gladstone Institute of Neurological Disease, San Francisco, San Francisco, CA 94158, USA; Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA; Neurosciences Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.
³ Department of Neuroscience, Erasmus MC, Rotterdam, the Netherlands; Department of Neurosurgery, Erasmus MC, Rotterdam, the Netherlands.
⁴ Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Pediatrics, Catholic University of Louvain, Louvain, Belgium.
⁵ Department of Neuroscience, Erasmus MC, Rotterdam, the Netherlands; Department of Neurosurgery, Erasmus MC, Rotterdam, the Netherlands; NIDOD Institute, Wilhelmina Children's Hospital, University Medical Center Utrecht and Brain Center Rudolf Magnus, Utrecht, the Netherlands.
⁶ Laboratory for Neurogenetics, RIKEN Brain Science Institute, Wako, Japan.
⁷ Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
⁸ Institut des Systèmes Intelligents et de Robotique (ISIR), Sorbonne University, 4 Place Jussieu, 75005 Paris, France.
⁹ Gladstone Institute of Neurological Disease, San Francisco, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA; Neurosciences Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: jeanne.paz@gladstone.ucsf.edu.

Abstract

Loss of function in the Scn1a gene leads to a severe epileptic encephalopathy called Dravet syndrome (DS). Reduced excitability in cortical inhibitory neurons is thought to be the major cause of DS seizures. Here, in contrast, we show enhanced excitability in thalamic inhibitory neurons that promotes the non-convulsive seizures that are a prominent yet poorly understood feature of DS. In a mouse model of DS with a loss of function in Scn1a, reticular thalamic cells exhibited abnormally long bursts of firing caused by the downregulation of calcium-activated potassium SK channels. Our study supports a mechanism in which loss of SK activity causes the reticular thalamic neurons to become hyperexcitable and promote non-convulsive seizures in DS. We propose that reduced excitability of inhibitory neurons is not global in DS and that non-GABAergic mechanisms such as SK channels may be important targets for treatment.

Keywords: Dravet syndrome; Nav1.1; SK current; Scn1a; epilepsy; optogenetics; reticular thalamic nucleus; seizures; thalamocortical circuits; thalamocortical oscillations.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Disease Models, Animal
Epilepsies, Myoclonic / physiopathology*
Humans
Mice
Seizures / physiopathology*
Thalamus / physiopathology*

Abstract

Publication types

MeSH terms

Grants and funding