Tau Negatively Regulates Translation and Olfactory Long-Term Memory, But Facilitates Footshock Habituation and Cytoskeletal Homeostasis

Although the involvement of pathological tau in neurodegenerative dementias is indisputable, its physiological roles have remained elusive in part because its abrogation has been reported without overt phenotypes in mice and This was addressed using the recently described and Mi{MIC} mutants and focused on molecular and behavioral analyses. Initially, we show that tau (dTau) loss precipitates dynamic cytoskeletal changes in the adult CNS and translation upregulation. Significantly, we demonstrate for the first time distinct roles for dTau in adult mushroom body (MB)-dependent neuroplasticity as its downregulation within α'β'neurons impairs habituation. In accord with its negative regulation of translation, dTau loss specifically enhances protein synthesis-dependent long-term memory (PSD-LTM), but not anesthesia-resistant memory. In contrast, elevation of the protein in the MBs yielded premature habituation and depressed PSD-LTM. Therefore, tau loss in dynamically alters brain cytoskeletal dynamics and profoundly affects neuronal proteostasis and plasticity. We demonstrate that despite modest sequence divergence, the tau (dTau) is a true vertebrate tau ortholog as it interacts with the neuronal microtubule and actin cytoskeleton. Novel physiological roles for dTau in regulation of translation, long-term memory, and footshock habituation are also revealed. These emerging insights on tau physiological functions are invaluable for understanding the molecular pathways and processes perturbed in tauopathies.