ACTIN-UP: TAU DELETION MODULATES PLASTICITY THROUGH SYNAPTIC ACTIN LEVELS AND DYNAMICS

Tau is a key protein that maintains the cytoskeletal architecture of neurons by cross-linking microtubules with actin filament networks, which are crucial for a range of physiological processes including synaptic plasticity. Early in tau pathology, there is accumulation of hyperphosphorylated tau at synapses that disrupts the actin-cytoskeleton eventually leading to loss of synapses. This raises the question of how tau regulates synaptic actin dynamics during synaptic weakening. We previously found that tau deletion enhances low frequency stimulation-induced long-term depression (LTD) in hippocampal slices prepared from juvenile male, but not female, tau knock-out (Mapt^-/-) rats. To assess the role of actin dynamics in this LTD enhancement, we applied latrunculin A (Lat A), which inhibits actin polymerization by sequestering globular actin. As reported previously, we found that Lat A enhanced LTD in male WT rats. However, the enhanced LTD present in male Mapt^-/- rats was reduced by LatA. Furthermore, stabilization of filamentous actin via inhibition of actin depolymerization with jasplakinolide had no effect on LTD in WT males but significantly attenuated the enhanced LTD in male Mapt^-/- rats. Consistent with these functional effects, male Mapt^-/- rats exhibited increased β/γ-actin levels and an elevated globular-to-filamentous actin ratio in synaptically-enriched fractions. Together, our findings suggest that tau constrains synaptic weakening by maintaining actin filament stability at synapses, and that loss of tau shifts synaptic actin towards a more dynamic, depolymerised state that facilitates exaggerated LTD.