PROJECT SUMMARY The autism spectrum disorders (ASDs) affect 1% of the world’s population. The syndromes in this diverse family of disorders share three core features: impaired social interactions, communication deficits, and repetitive behaviors. In the United States, 1 in 68 children are now diagnosed with ASDs, a drastic increase over the last few decades. Despite the perceived “epidemic” of ASDs, there are few effective treatments. In roughly 30% of patients, ASD is associated with epilepsy that is often also refractory to available treatments. Thus, there is an urgent need to develop better treatments for these challenging conditions. The core symptoms of ASDs are common in Dravet syndrome, an intractable epilepsy with onset in early childhood. We recently demonstrated that genetic reduction of tau, a microtubule-associated protein implicated in neurodegenerative disorders, prevents or markedly reduces epileptic seizures, cognitive deficits, and premature mortality in a model of Dravet syndrome (Scn1aRX/+ mice). More surprisingly, we found that tau reduction ameliorated social impairments, communication deficits, and repetitive behaviors in these mice. Genetic reduction of tau also ameliorated similar communication deficits and repetitive behaviors in a separate model of ASD (Cntnap2–/– mice). Encouragingly, genetic tau reduction was well tolerated throughout the lifespan, tau knockdown initiated in adulthood also did not cause obvious adverse effects, and complete ablation was not necessary, as even partial tau reduction provided substantial benefit. These data led to our central hypothesis that tau reduction counteracts ASD pathogenesis and may be developed into an effective treatment for several of these conditions. However, several key issues must be resolved before this strategy is ready for clinical development. To determine whether ASD subtypes that do not include epilepsy may benefit from such a treatment approach, we will examine whether genetic ablation of tau prevents or reduces autism-like behaviors in a third independent mouse model of genetically determined ASD that does not develop epilepsy, Shank3B–/– mice. In addition, an ideal ASD therapy would be effective even if it was administered after symptoms become apparent. To test this possibility, we will knock down cerebral tau expression in Scn1aRX/+ mice with antisense oligonucleotides after autism-like behaviors have become manifest. Finally, we will test hypotheses about the molecular, cellular, and circuit mechanisms by which tau reduction counteracts the core symptoms of ASD. In the long run, our aim is to enable tau reduction to be developed into a treatment for multiple ASDs. By determining the consequences of tau reduction on molecular regulato...