Accumulation of hyperphosphorylated tau protein in cortical neurons is one of important hallmarks for Alzheimer's disease (AD) and other tauopathies. Studies using tau over-expression mice and AD brains have shown that degree of the tau accumulation in neurons correlates with the level of their synaptic deficits. On the other hand, tau gene knockout mouse shows a deficit in long-term synaptic depression (LTD) of the hippocampal synapses, suggesting that tau plays an essential role in synaptic plasticity. However, little is known about the role of tau in LTD and the relationship between LTD and tau-accumulation mechanism.
To elucidate role of tau on LTD, we examined field EPSPs using organotypic hippocampal slice cultures of wild-type and tau knockout mice. In the hippocampal slices of wild-type mouse, NMDA induces NMDA receptor-dependent LTD (NMDAR-LTD) and DHPG induces metabotropic glutamate receptor-dependent LTD. In the tau knockout mouse, NMDA could induce depression of fEPSP during the first 30 minutes but could not maintain that depression for a long term. The fEPSP gradually returned to baseline level in 1 hour. DHPG also elicited normal LTD in tau knockout mouse. These findings indicate that tau is required for NMDAR-LTD maintenance following induction. Next, we investigated changes in biochemical feature of tau after NMDA treatment. This experiment revealed that tau level in the crude synaptosomal (P2) fraction increased at 30 minutes after NMDA treatment. The increased level of tau in the P2 fraction may be due to decreased solubility of tau in solution or change in its intracellular distribution. Our results demonstrate a novel role of tau in mechanism of the NMDAR-LTD.