Tau reduction prevents disease in a mouse model of Dravet syndrome. Issue 3 (13th August 2014)

• Record Type: Journal Article
• Authors: Gheyara, Ania L.; Ponnusamy, Ravikumar; Djukic, Biljana; Craft, Ryan J.; Ho, Kaitlyn; Guo, Weikun; Finucane, Mariel M.; Sanchez, Pascal E.; Mucke, Lennart
• Is Part Of: Annals of neurology. Volume 76:Issue 3(2014:Sep.)
• Page Start: 443
• Page End: 456
• Publication Date: 2014-08-13
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.24230
• Languages: English
• ISSNs: 0364-5134

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ana24230-sec-0001" sec-type="section"> <title>Objective</title> <p>Reducing levels of the microtubule‐associated protein tau has shown promise as a potential treatment strategy for diseases with secondary epileptic features such as Alzheimer disease. We wanted to determine whether tau reduction may also be of benefit in intractable genetic epilepsies.</p> </sec> <sec id="ana24230-sec-0002" sec-type="section"> <title>Methods</title> <p>We studied a mouse model of Dravet syndrome, a severe childhood epilepsy caused by mutations in the human <italic>SCN1A</italic> gene encoding the voltage‐gated sodium channel subunit Na<sub>v</sub>1.1. We genetically deleted 1 or 2 <italic>Tau</italic> alleles in mice carrying an Na<sub>v</sub>1.1 truncation mutation (R1407X) that causes Dravet syndrome in humans, and examined their survival, epileptic activity, related hippocampal alterations, and behavioral abnormalities using observation, electroencephalographic recordings, acute slice electrophysiology, immunohistochemistry, and behavioral assays.</p> </sec> <sec id="ana24230-sec-0003" sec-type="section"> <title>Results</title> <p>Tau ablation prevented the high mortality of Dravet mice and reduced the frequency of spontaneous and febrile seizures. It reduced interictal epileptic spikes in vivo and drug‐induced epileptic activity in brain slices ex vivo. Tau ablation also prevented biochemical changes in the hippocampus indicative of epileptic activity and ameliorated abnormalities in learning and memory, nest building, and open field behaviors in Dravet mice. Deletion of only 1 <italic>Tau</italic> allele was sufficient to suppress epileptic activity and improve survival and nesting performance.</p> </sec> <sec id="ana24230-sec-0004" sec-type="section"> <title>Interpretation</title> <p>Tau reduction may be of therapeutic benefit in Dravet syndrome and other intractable genetic epilepsies. Ann Neurol 2014;76:443–456</p> </sec> </abstract>