Estradiol and the relationship between dendritic spines, NR2B containing NMDA receptors, and the magnitude of long-term potentiation at hippocampal CA3–CA1 synapses

Abstract

Summary When circulating estrogen levels decline as a natural consequence of menopause and aging in women, there is an increased incidence of deficits in working memory. In many cases, these deficits are rescued by estrogen replacement therapy. These clinical data therefore highlight the importance of defining the biological pathways linking estrogen to the cellular substrates of learning and memory. It has been known for nearly two decades that estrogen enhances dendritic spine density on apical dendrites of CA1 pyramidal cells in hippocampus, a brain region required for learning. Interestingly, at synapses between CA3-CA1 pyramidal cells, estrogen has also been shown to enhance synaptic NMDA receptor current and the magnitude of long term potentiation, a cellular correlate of learning and memory. Given that synapse density, NMDAR function, and long term potentiation at CA3-CA1 synapses in hippocampus are associated with normal learning, it is likely that modulation of these parameters by estrogen facilitates the improvement in learning observed in rats, primates and humans following estrogen replacement. To facilitate the design of clinical strategies to potentially prevent or reverse the age-related decline in learning and memory during menopause, the relationship between the estrogen-induced morphological and functional changes in hippocampus must be defined and the role these changes play in facilitating learning must be elucidated. The aim of this report is to provide a summary of the proposed mechanisms by which this hormone increases synaptic function and in doing so, it briefly addresses potential mechanisms contributing to the estrogen-induced increase in synaptic morphology and plasticity, as well as important future directions.

Diminished Nap Effects on Memory Consolidation Are Seen Under Oral Contraceptive Use

“…In the hippocampus and the medial prefrontal cortex, estrogen increases dendritic spines, and an increase in spine density has been associated with learning and memory [9,64]. Estrogens upregulate adult hippocampal neurogenesis and synaptic protein levels in the hippocampus as well as enhance synaptic NMDA receptor current and the magnitude of long-term potentiation, a cellular correlate of learning and memory [14,15,16]. …”

“…These latter tasks are positively influenced by the hormones estrogen and progesterone. In contrast, tasks with a male advantage are affected negatively by the same hormones [12,13,14,15,16]. Furthermore, use of OCs influences memory encoding: Females showed enhanced verbal memory during the active OC phase [17].…”

Scopolamine Produces Larger Antidepressant and Antianxiety Effects in Women Than in Men

“…Estrogen has been shown to modulate the functional state of the cholinergic system by increasing choline acetyltransferase (ChAT) activity and by increasing the release of Ach Pongrac et al, 2004). Researchers have also demonstrated that estrogen enhances NMDAR function by increasing NMDAR binding, at least in some brain regions, possibly by increasing the density of dendritic spines that express NMDAR (McEwen et al, 2001;Smith et al, 2009;Woolley and McEwen, 1994). Moreover, Daniel and Dohanich (2001) demonstrated that the influence of estrogen on NMDA receptor function is mediated specifically via M2 receptors.…”

Sex steroid hormones matter for learning and memory: estrogenic regulation of hippocampal function in male and female rodents

“…Perhaps, the most notable effect of E 2 on hippocampal physiology is its ability to potentiate NMDA-dependent LTP in female CA3-CA1 synapses (for reviews, see Foy 2001;Woolley 2007;Smith et al 2009). LTP results in a persistent increase in synaptic excitability thought to underlie memory formation.…”