Arc might mediate LTD by regulating AMPAR endocytosis. In fact, mGluR-induced LTD requires Arc for endocytosis of AMPARs [29]. Arc expression decreases the amplitude of AMPAR-mediated synaptic currents by acting through endophilin 1 and dynamin 2 to promote AMPAR endocytosis [13,14] (Figure 2). It is unclear if Arc acts on the GluA1 or GluA2 subunits of AMPARs. It is also possible that both subunits are regulated by Arc, and discrepancies between studies could be due to the differing sensitivities of the techniques used [13,14]. Exactly how Arc regulates the endocytic machinery is unknown, and no direct evidence shows that low frequency stimulation causes Arc to localize to endophilin and dynamin. To fully explain how Arc can mediate both LTP and LTD, additional research is needed to better understand the cellular functions of Arc and how they are regulated by different stimuli.