Sodium Channels and Dravet Syndrome, an Intractable Childhood Epilepsy
William A. Catterall, Department of Pharmacology, University of Washington
Background. Genetically dominant loss-of-function mutations in the type-1 brain sodium channel NaV1.1 cause Dravet Syndrome, which includes intractable epilepsy, ataxia, sleep and circadian disorders, severe cognitive deficit, autistic-like behaviors, and frequent premature death. We developed a mouse model of Dravet Syndrome that recapitulates all of its features. We found that NaV1.1 channels are particularly important for electrical excitability of GABAergic interneurons and that all of the manifestations of this disease are caused by failure of firing of GABAergic interneurons and disinhibition of neural circuits.
Research Project. Our current research is aimed at understanding the defects in neural circuits that lead to the different manifestations of Dravet Syndrome and at developing novel, science-based therapies. We are using the Cre-Lox method to mutate NaV1.1 in specific cell types and in specific anatomical regions in mice. We record the functional effects of these gene deletions on neurons and neural circuits in brain slices using patch clamp and in whole animals using tetrodes. We are using optogenetics and chemogenetics to rescue the impaired firing of specific disease-relevant classes GABAergic neurons. We are testing novel pharmacological approaches that are based on our emerging understanding of the detailed pathophysiology of this disease. We hope that our research will lead to new understanding and practical therapies for this devastating disease.
See Rubinstein, Brain 2015; Kaplan, PNAS 2017; Catterall, Current Opinion in Physiology 2018
Basic molecular and cellular biology, whole-cell voltage clamp physiology, and brain slice recording are required.
Experience with in vivo electrophysiology and behavior in rodents is valuable.
We seek enthusiastic well-trained neuroscientists who are excited about the opportunity to analyze a devastating disease at cellular, circuit, and systems levels and develop novel therapeutic approaches.
Internal Number: PD NaDS 1
About University of Washington
The University of Washington is a major biomedical research institution in Seattle, WA. It has leading research and teaching programs in all aspects of neuroscience.