Intracellular accumulation of the microtubule-associated protein tau is a hallmark of Alzheimer disease. Alternative splicing of the gene encoding tau can generate tau isoforms with three repeat domains (3R) or four repeat domains (4R), and it has been hypothesized that an excess of 4R tau is toxic. Schoch et al. used antisense oligonucleotides to switch the predominant tau splice isoform from 3R to 4R in mice. This resulted in an increase in pentylenetetrazole-induced seizure severity, impaired nesting activity, and increased tau phosphorylation and aggregation, thus demonstrating pathological effects of elevated levels of the 4R isoform.