Developmental Changes in Estrogen Receptors in Mouse Cerebral Cortex between Birth and Postweaning: Studied by Autoradiography with llβ-Methoxy-16α- [¹²⁵I]Iodoestradiol*

Abstract

The presence of estrogen receptor cells in postnatal cerebral cortex and their topographical and numerical changes between birth and postweaning were examined. On postnatal days 0, 2, 8, 12, 18, and 25, six mice (three males and three females) were injected sc with 0.25 microgram/100 g BW 11 beta-methoxy-16 alpha-[125I]iodoestradiol [( 125I]MIE2). Two additional males on postnatal day 2 were each sc injected with 250 micrograms/100 g BW 17 beta-estradiol 1 h before radiolabeled ligand to establish the specificity of nuclear label. Two hours after the injection of [125I]MIE2 brains were frozen, and 4-microns sections were thaw-mounted and processed for autoradiography. Autoradiograms were exposed for 1-45 days, and cortical cells with nuclear uptake and retention of [125I]MIE2 were evaluated at the levels of the frontal pole, preoptic area, and central and posterior hypothalamus. At birth, cells with nuclear label were found predominantly in deep cortical layers. Between birth and postnatal day 2, the number of labeled cells increased in deep and intermediate laminae and first appeared in certain superficial regions. By day 8, labeled cells were concentrated in laminae II-VI of the cingulate/paracingulate and suprarhinal cortex. On day 12, labeling in laminae V and VI declined to a few cells, while a concentration of labeled cells remained in laminae II and III of the cingulate/paracingulate and suprarhinal regions. With subsequent development, an attenuation in labeling at all cortical levels was observed. By day 25, a small cluster of labeled cells remained in lamina II and III of the anterior cingulate, paracingulate, and suprarhinal regions, with additional labeled cells scattered throughout the remaining cortex. Competition with unlabeled 17 beta-estradiol reduced nuclear concentration of ligand in all cortical layers and demonstrated the specificity of [125I]MIE2 for the estrogen receptor. These results show the extensive presence of estrogen target cells in the early postnatal cortex and a profound change in topography and number of target cells during the postnatal period. These findings further suggest an important role for estrogen in the development of certain cortical neurons, possibly involving neuronal differentiation, cell positioning, and connectivity.

Changes in estrogen receptor-alpha mRNA in the mouse cortex during development

“…In early postnatal development of the mouse, estrogen binding is high in the cortex and diminishes as the animal approaches puberty [28,30]. This correlates with the drastic decrease in ERα mRNA expression shown in the current study.…”

“…Other data suggests that estrogenbound α-fetoprotein accumulates in the brain and is the source of estrogens in the female brain [8,31]. In either case, there was no difference in estradiol binding activity between male and female mice [28]. Similarly, we found that the pattern of ERα and ERβ mRNA expression in the developing mouse cortex shows no difference between males and females, suggesting that its regulation is not due to estrogen influences.…”

“…Estrogen binding studies were performed prior to the discovery of ERβ, thus making it difficult to determine if ERα and/or ERβ were responsible for the decrease in estrogen binding in the cortex [28]. This study indicates that the developmental decrease in estradiol binding in the mouse cortex is likely a result of a decline ERα mRNA and not ERβ mRNA.…”

“…Receptor binding studies have demonstrated that early in postnatal life of male and female rodents, estrogen binds not only in reproductive areas of the brain, such as the hypothalamus, but also shows a unique binding pattern in the cortex [28,30]. In early postnatal development there are high levels of estradiol binding in the cortex and hippocampus and as the animal approaches puberty, this diminishes.…”

Sex‐Related Differences in Dendritic Branching of Cells in the Prefrontal Cortex of Rats

“…Shughrue et a/. (16) have shown a dramatic increase in the concentration of receptors from birth through postnatal Day 8 (PN8) and a change in topography from deep layers of cortex to concentrations in specific regions. As has been pointed out previously these receptors begin to diminish in number thereafter and appear to have almost disappeared by PN25 (20,21), suggesting that they may play a role in the development of the cortex.…”