Estrogen and Aging Affect the Subcellular Distribution of Estrogen Receptor-α in the Hippocampus of Female Rats

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Abstract
Estrogen replacement increases both the number of dendritic spines and the density of axospinous synapses in the hippocampal CA1 region in young rats, yet this is attenuated in aged rats. The estrogen receptor-α (ER-α) is localized within select spines of CA1 pyramidal cells in young animals and thus may be involved locally in this process. The present study investigated the effects of estrogen on the ultrastructural distribution of ER-α in the CA1 of young (3–4 months) and aged (22–23 months) Sprague Dawley rats using postembedding immunogold electron microscopy. Within dendritic spines, most ER-α immunoreactivity (IR) was seen in plasmalemmal and cytoplasmic regions of spine heads, with a smaller proportion within 60 nm of the postsynaptic density. In presynaptic terminals, ER-α-IR was clustered and often associated with synaptic vesicles. Significant effects of both aging and estrogen were observed. Quantitative analysis revealed that nonsynaptic pools of ER-α-IR within the presynaptic and postsynaptic compartments were decreased (35 and 27%, respectively) in the young estrogen-replaced animals compared with those that received vehicle. Such localized regulation of ER-α in response to circulating estrogen levels might directly affect synaptic signaling in CA1 pyramidal cells. No estrogen treatment-related differences were observed in the aged animals. However, 50% fewer spines contained ER-α in the aged compared with young hippocampus. These data suggest that the decreased responsiveness of hippocampal synapses to estrogen in aged animals may result from age-related decrements in ER-α levels and its subcellular localization vis-à-vis the synapse. Such a role for spinous ER-α has important implications for age-related attenuation of estrogen-induced hippocampal plasticity.