It is well established that activity dependent changes in the efficacy of hippocampal synaptic transmission is a cellular correlate of learning and memory. Trafficking of AMPA-receptors to and from synapses is an important mechanism underlying hippocampal synaptic plasticity. Increasing evidence implicates hormonal systems in the influence of AMPA-receptor trafficking, and thus synaptic plasticity. Estrogen, primarily known for its reproductive effects, has long been implicated in influencing cognitive processes. Estrogen receptors (ERs), classically found in the nucleus, act as ligand-activated transcription factors in mediating genomic responses. ERs can also mediate rapid non-genomic responses via membrane-associated ERs. Two well characterised ERs, ERα and ERβ, are widely expressed in the hippocampus. However, little is known about how these ER subtypes influence cognitive processes. Moreover, the novel G-protein-coupled receptor, GPR30, has been identified as an estrogen target, and recent studies suggest possible cross-talk between ERα and GPR30.1 In pilot studies, we have found that the broad-spectrum agonist, 17β-estradiol, induces bidirectional changes in AMPA-receptor trafficking. In addition, recent studies have implicated ERβ-activation in improving performance in hippocampal-dependent memory tasks and increasing key synaptic proteins such as the AMPA-receptor subunit GluR1. In this study, we have examined how estrogen influences AMPA-receptor trafficking by utilising ERα-, ERβ-, and GPR30-selective agonists in an immunocytochemical approach. We show that activation of ERα and GPR30 results in a decrease in GluR1 surface expression likely to be mediated by an exocytosis-dependent mechanism, and that activation of ERβ results in an increase in GluR1 surface expression likely to be mediated by an endocytosis-dependent mechanism. In addition, we demonstrate that the effects of GPR30-activation on GluR1 surface expression are unlikely to be due to ERα-activation. These findings have important implications for the role of estrogen in cognitive decline and neurodegenerative disorders.