Title : Physiological and pathophysiological implications of synaptic tau

Tauopathies encompass a broad range of neurodegenerative diseases featuring extensive neuronal death and cognitive decline. However, research over the past thirty years has failed to significantly advance our understanding of how tau causes dementia, limiting the design of rational therapeutics. It has become evident that we need to expand our understanding of tau in physiology, in order to delineate how tau may contribute to pathology. This review will discuss recent evidence that has uncovered a novel aspect of tau function, based on its previously uncharacterised localisation to the synapse. Here, multiple streams of evidence support a critical role for synaptic tau in the regulation of synapse physiology. In particular, long-term depression, a form of synaptic weakening, is dependent on the presence of tau in hippocampal neurons. The regulation of tau by specific phosphorylation events downstream of GSK-3β activation appears to be integral to this signalling role. We will also describe how the regulation of synapse physiology by tau and its phosphorylation may inform our understanding of tauopathies and co-morbid diseases. This work should provide a platform for future tau biology research in addition to therapeutic design.