Tau reduction prevents disease in a mouse model of Dravet syndrome

Objective: Tau, a protein found in neurons, is important for providing them mechanical support and structure. Disruptions in tau have been implicated in neurological disorders like dementia and Alzheimer's disease. Previous studies with experimental rodents have shown that reduction of tau protein is beneficial in epilepsy. The current study was done to observe whether reduction of tau would be beneficial in Dravet Syndrome (DS). DS is a disorder caused by a mutation in the SCN1A gene – this gene codes for a sodium channel called NaV1.1. DS is characterized by severe, intractable seizures (seizures that do not respond well to anti-epileptic drugs) and behavioral and cognitive deficits. Indeed, DS is one of the most drug-resistant forms of epilepsy. Since the gene responsible for DS is known, it is possible to simulate the exact deficit in mice in order to study their characteristics to eventually find better drugs for DS. To study the role of tau in DS mice, the scientists used a genetic technique to reduce tau. The hypothesis was that mice with DS and reduced tau would have fewer seizures as compared to DS mice with normal amounts of tau.

Results: Individuals with DS can experience SUDEP (sudden unexpected death in epilepsy). Similarly, mice with DS exhibit mortality. Remarkably, mice with DS and reduced tau showed reduced mortality suggesting the protective effects of tau reduction. Interictal spikes in the electroencephalogram have been shown to be hallmarks of the epileptic brain both in the clinic and in the lab. Mice with DS and reduced tau had fewer interictal spikes and seizures, as well as fewer behavioral abnormalities as compared to mice with DS and intact tau. When the scientists looked at the brains of DS mice with reduced tau, there were fewer markers indicative of epilepsy as compared to DS mice with intact tau.

Interpretation: This study shows that reduction of tau in DS mice is protective against seizures and behavioral abnormalities. These results are quite exciting not only for DS but also for refractory epilepsy. Approximately one-third of individuals with epilepsy do not respond well to currently available antiepileptic drugs; in these cases, reduction of tau could be useful. However, how to reduce tau in a safe way needs to be further investigated.

Short summary for scientists: Preclinical studies have shown that ablation of tau is protective against seizures in Alzheimer's disease- a neurological condition where seizures are not uncommon. In this study, the scientists wanted to see if reduction of tau would be beneficial in Dravet Syndrome (DS) as well. Using in vivo and ex vivo physiology, behavioral studies and seizure monitoring, it was found that reduction of tau was indeed protective against seizures and associated behavioral comorbidites in DS mice.

Summary for specialists