Antithetical roles of tau in hippocampal long-term synaptic depression in rats versus mice

Synaptic dysfunction is a primary feature of tauopathies, a group of major neurodegenerative diseases that includes Alzheimer's disease. However, the normal synaptic functions of tau are poorly understood. Since rats provide advantages over mice for understanding human tau, such as expressing six tau isoforms and showing more robust signs of tau pathology, as well as offering a richer behavioural repertoire, we developed a tau knockout (Mapt KO) rat line. We primarily investigated the impact of tau elimination on long-term synaptic depression (LTD)-a form of synaptic weakening that tau mediates in mice. Low-frequency stimulation of hippocampal Schaffer collateral-CA1 synapses revealed a robust enhancement of LTD in Mapt KO rats relative to WT littermates. In contrast, in interleaved experiments, Mapt KO mice exhibited reduced LTD compared to WT littermates, in line with previous reports. Together, our findings demonstrate a species-dependent role for endogenous tau in regulating hippocampal LTD, promoting it in mice yet constraining it in rats. Therefore, the functions of tau are not necessarily conserved in rodents, underscoring the importance of animal model choice.