Actions of estrogens are mediated via estrogen receptor ERa and ERß, both of which are widely expressed in the CNS. Estrogens have long been implicated in influencing memory processes, yet the molecular mechanisms underlying these effects and the roles of the estrogen receptors alpha (ERa) and beta (ERß) remain unclear. This symposium will start with an overview of estrogen and memory formation and the mechanisms of its actions, including effects on cell morphology, synapse formation, cellular signaling, and neuronal excitability. Physiologic and pharmacologic forms of estrogen affect cognitive behavior in mammals, which may be applicable to treatment of diseases with impaired cognition. To elucidate the mechanism underlying estrogens actions, the meeting will investigate how estrogen rapidly modifies the structure of synaptic spines and their underlying cytoskeleton. Acute infusions of ß-estradiol cause a rapid modest, and reversible increase in the size of field EPSPs and promote theta burst-induced long-term potentiation in hippocampal area CA1. These acute effects on synaptic responses and LTP involve signaling pathways leading to actin polymerization within dendritic spines. Complementing these studies, the effects of estrogen on hippocampal synaptic plasticity and memory, as mediated through ERß, will be examined. Selective ERß agonists increase key synaptic proteins and induce morphological changes in hippocampal neurons in vivo, enhance LTP and improve performance in hippocampus-dependent memory tasks. In addition, the differential impact of ERa and ERß activation on AMPA-receptor subunit GluR1 and associated proteins will be discussed. This data set suggests that targeting ERß may have therapeutic potential without the feminizing effects of estrogen. New insights will be presented from studies of young and aged female non-human primates on the interactive effects of aging and estrogen treatment on neuronal architecture and synaptic organization in hippocampus and prefrontal cortex. These data have important implications for the neurobiological basis of cognitive aging and also demonstrate the potential for protection against these age-related synaptic alterations and the related cognitive decline. This session will show the critical importance of estrogen signaling for memory formation and start to describe recent advances in dissecting out the pathways underlying these effects. This research should have a profound impact on how we consider estrogen-based therapies for diseases with memory deficits.