Tau is a microtubule binding protein and has been identified as a key molecule in Alzheimer’s disease (AD), as well as other tauopathies (Ballatore et al., 2007). Though tau is primarily located in axons, the entirety of its physiological roles are yet to be clearly defined. Given the dysregulation of the synapse in AD pathology (Selkoe, 2002), we investigated a possible physiological synaptic function of tau. We studied synaptic plasticity in the rat hippocampus, and found a selective deficit in long-term depression (LTD) as a result of RNAi knockdown of tau in vitro. Furthermore, we found that the induction of LTD is associated with the phosphorylation of tau, and this is required for the activation of key AMPA receptor internalisation mechanisms. These findings demonstrate that tau has a critical function in AMPA receptor trafficking during LTD and suggest that tauopathies may result from an aberrant form of LTD in the CNS.