Augmented Reticular Thalamic Bursting and Seizures in Scn1a-Dravet Syndrome
Ritter-Makinson, Stefanie; Clemente-Perez, Alexandra; Higashikubo, Bryan; Cho, Frances S.; Holden, Stephanie S.; Bennett, Eric; Chkaidze, Ana; Eelkman Rooda, Oscar H.J.; Cornet, Marie Coralie; Hoebeek, Freek E.; Yamakawa, Kazuhiro; Cilio, Maria Roberta; Delord, Bruno; Paz, Jeanne T.
(2019) Cell Reports, volume 26, issue 1, pp. 54 - 64.e6
(Article)
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
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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.
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Keywords: Animals, Disease Models, Animal, Epilepsies, Myoclonic/physiopathology, Humans, Mice, Seizures/physiopathology, Thalamus/physiopathology, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.
ISSN: 2211-1247
Publisher: Cell Press
Note: Funding Information: S.R.-M. is supported by the American Epilepsy Society and the Dravet Syndrome Foundation Postdoctoral Research Fellowship. B.H. is supported by the American Epilepsy Society Postdoctoral Research Fellowship. J.T.P. is supported by NIH/NINDS R01NS096369, the DoD, the NSF, Gladstone Institutes, the Kavli Institute for Fundamental Neuroscience, the Michael Prize, and the Jewett Foundation. A.C.-P. and F.S.C. are supported by NSF Graduate Research Fellowships. S.S.H. is supported by the ARCS Foundation and Weill Institute Foundation scholarships. O.H.J.E.R. and F.E.H. are supported by Dutch NWO-ALW VIDI 016.121.346 and ZON-MW TOPGO.L.10.066 and the Erasmus MC MRace. M.-C.C. is supported by the Belgian American Education Foundation. We thank Scott Brovarney and Juan Alcauter for help with animal husbandry and technical help with histology. We thank Jordan Sorokin and John Huguenard for sharing their MATLAB code for the analysis of evoked thalamic oscillations. We thank Meredith Calvert from the Gladstone Histology & Light Microscopy Core for experimental and technical support. We thank Drs. Daniel Lowenstein and Adam Numis for their feedback on the interpretation of the human EEG and Brett Mensh for critical feedback on the manuscript. Funding Information: S.R.-M. is supported by the American Epilepsy Society and the Dravet Syndrome Foundation Postdoctoral Research Fellowship . B.H. is supported by the American Epilepsy Society Postdoctoral Research Fellowship . J.T.P. is supported by NIH/NINDS R01NS096369 , the DoD , the NSF , Gladstone Institutes , the Kavli Institute for Fundamental Neuroscience , the Michael Prize , and the Jewett Foundation . A.C.-P. and F.S.C. are supported by NSF Graduate Research Fellowships. S.S.H. is supported by the ARCS Foundation and Weill Institute Foundation scholarships. O.H.J.E.R. and F.E.H. are supported by Dutch NWO-ALW VIDI 016.121.346 and ZON-MW TOPGO.L.10.066 and the Erasmus MC MRace . M.-C.C. is supported by the Belgian American Education Foundation . We thank Scott Brovarney and Juan Alcauter for help with animal husbandry and technical help with histology. We thank Jordan Sorokin and John Huguenard for sharing their MATLAB code for the analysis of evoked thalamic oscillations. We thank Meredith Calvert from the Gladstone Histology & Light Microscopy Core for experimental and technical support. We thank Drs. Daniel Lowenstein and Adam Numis for their feedback on the interpretation of the human EEG and Brett Mensh for critical feedback on the manuscript. Publisher Copyright: © 2018 The Authors
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