Tau reduction prevents disease in a mouse model of Dravet syndrome.

Abstract:

OBJECTIVE: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. METHODS:We studied a mouse model of Dravet syndrome, a severe childhood epilepsy caused by mutations in the human SCN1A gene encoding the voltage-gated sodium channel subunit Nav 1.1. We genetically deleted 1 or 2 Tau alleles in mice carrying an Nav 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. RESULTS: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 Tau allele was sufficient to suppress epileptic activity and improve survival and nesting performance. INTERPRETATION:Tau reduction may be of therapeutic benefit in Dravet syndrome and other intractable genetic epilepsies.

journal_name

Ann Neurol

journal_title

Annals of neurology

authors

Gheyara AL,Ponnusamy R,Djukic B,Craft RJ,Ho K,Guo W,Finucane MM,Sanchez PE,Mucke L

doi

10.1002/ana.24230

subject

Has Abstract

pub_date

2014-09-01 00:00:00

pages

443-56

issue

3

eissn

0364-5134

issn

1531-8249

journal_volume

76

pub_type

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