Estrogen-mediated effects on cognition and synaptic plasticity: What do estrogen receptor knockout models tell us?

A plethora of evidence supports a beneficial role of estrogen in the brain. However, while these effects are hypothesized to be driven via the two main forms of estrogen receptors (ERα and ERβ), the mechanism through which these receptors mediate estrogen's effects on cognition and plasticity remain unclear. Estrogen receptors are heterogeneously expressed in many cognition sensitive regions of the brain, have the ability to dimerize and heterodimerize, and are localized to both neurons and glia. In addition, while many of the known actions of estrogen through their receptor are mediated via the classical genomic regulatory mechanism of gene transcription, rapid non-genomic action of estrogens are also gaining relevance. These complex events make the mechanistic understanding of estrogen effects challenging. The development of transgenic estrogen receptor knockout mouse models has provided some much needed insight on the role of these receptors in mediating estrogen effects on cognition and synaptic plasticity. This review provides an overview of estrogen receptors in the brain and an update of knowledge gained from transgenic knockout models on cognition and synaptic plasticity.