Tau T205 phosphorylation modulates engram cell recruitment and remote memory in mice

Memory loss is linked to failure of the engram, the physical substrate associated with a specific memory. Tau is a microtubule associated protein best known for its central role in neurodegenerative dementias, yet its physiological function in memory formation remains poorly understood. In this work, we show that tau is crucial for forming long lasting memories in mice. Site-specific tau phosphorylation at threonine-205 (T205) is induced by memory encoding and is required for remote memory formation. Tau T205 phosphorylation regulates engram cell, physical unit of memory storage, recruitment and constrains extraneous local cell activation, thereby promoting efficient memory recall. Tau selectively links sensory cue presentations to the encoding ensemble, as optogenetic retrieval of remote memory is tau-independent. Pathogenic tau within active cell ensembles induces aberrant local activation and causes anterograde or retrograde amnesia when present during an encoding or recall time window, respectively. Together, these findings identify a direct physiological role for tau in engram ensemble regulation and establish a mechanistic link between tau dysfunction and memory loss. Memory loss reflects failure of the engram, the cell ensemble that stores memory. Here, the authors show that site-specific phosphorylation of tau, a protein associated with Alzheimer’s disease, coordinates activity of cells linked to long-lasting memories in mice.