TAU ablation in excitatory neurons and postnatal TAU knockdown reduce epilepsy, SUDEP, and autism behaviors in a Dravet syndrome model

Intracellular accumulation of TAU aggregates is a hallmark of several neurodegenerative diseases. However, global genetic reduction of TAU is beneficial also in models of other brain disorders that lack such TAU pathology, suggesting a pathogenic role of nonaggregated TAU. Here, conditional ablation of TAU in excitatory, but not inhibitory, neurons reduced epilepsy, sudden unexpected death in epilepsy, overactivation of the phosphoinositide 3-kinase–AKT-mammalian target of rapamycin pathway, brain overgrowth (megalencephaly), and autism-like behaviors in a mouse model of Dravet syndrome, a severe epileptic encephalopathy of early childhood. Furthermore, treatment with a TAU-lowering antisense oligonucleotide, initiated on postnatal day 10, had similar therapeutic effects in this mouse model. Our findings suggest that excitatory neurons are the critical cell type in which TAU has to be reduced to counteract brain dysfunctions associated with Dravet syndrome and that overall cerebral TAU reduction could have similar benefits, even when initiated postnatally. Description TAU ablation in excitatory neurons and postnatal knockdown of brain TAU reduce epilepsy, early death, and autism behaviors in a Dravet syndrome model. Targeting TAU in Dravet’s Dravet syndrome (DS) is a genetic severe developmental epileptic disorder that can also result in autistic behaviors. Accumulating evidence has shown that reducing TAU can exert therapeutic effects in models of autism spectrum disorders. Here, Shao et al. evaluated the effects of cell type-specific TAU ablation in a rodent model of DS. The authors found that selective Tau depletion in excitatory neurons reduced seizures and mortality in DS mice. Similarly, postnatal administration of a TAU-lowering antisense oligonucleotide reduced disease symptoms and improved survival. The results suggest that the presence of TAU in excitatory cells might play a disease-promoting role in DS and could be targeted to obtain therapeutic benefits.