Female hippocampal estrogens have a significant correlation with cyclic fluctuation of hippocampal spines

Estradiol is the most potent and ubiquitous member of a class of steroid hormones called estrogens. Fetuses and newborns are exposed to estradiol derived from their mother, their own gonads, and synthesized locally in their brains. Receptors for estradiol are nuclear transcription factors that regulate gene expression but also have actions at the membrane, including activation of signal transduction pathways. The developing brain expresses high levels of receptors for estradiol. The actions of estradiol on developing brain are generally permanent and range from establishment of sex differences to pervasive trophic and neuroprotective effects. Cellular end points mediated by estradiol include the following: 1) apoptosis, with estradiol preventing it in some regions but promoting it in others; 2) synaptogenesis, again estradiol promotes in some regions and inhibits in others; and 3) morphometry of neurons and astrocytes. Estradiol also impacts cellular physiology by modulating calcium handling, immediate-early-gene expression, and kinase activity. The specific mechanisms of estradiol action permanently impacting the brain are regionally specific and often involve neuronal/glial cross-talk. The introduction of endocrine disrupting compounds into the environment that mimic or alter the actions of estradiol has generated considerable concern, and the developing brain is a particularly sensitive target. Prostaglandins, glutamate, GABA, granulin, and focal adhesion kinase are among the signaling molecules co-opted by estradiol to differentiate male from female brains, but much remains to be learned. Only by understanding completely the mechanisms and impact of estradiol action on the developing brain can we also understand when these processes go awry.

Gonadal steroids are known to influence hippocampal physiology in adulthood. It is presently unknown whether gonadal steroids influence the morphology of hippocampal neurons in the adult intact rat brain. In order to determine whether female sex hormones influence hippocampal morphology in the intact adult, we performed Golgi impregnation on brains from ovariectomized rats and ovariectomized rats which received estradiol or estradiol and progesterone replacement. Removal of circulating gonadal steroids by ovariectomy of adult female rats resulted in a profound decrease in dendritic spine density in CA1 pyramidal cells of the hippocampus. Estradiol replacement prevented the observed decrease in dendritic spine density; progesterone augmented the effect of estradiol within a short time period (5 hr). Ovariectomy or gonadal steroid replacement did not affect spine density of CA3 pyramidal cells or granule cells of the dentate gyrus. These results demonstrate that gonadal steroids are necessary for the maintenance of normal adult CA1 hippocampal pyramidal cell structure. The short time course required to observe these effects (3 d for the estradiol effect and 5 hr for the progesterone effect) implies that CA1 pyramidal cell dendritic spine density may fluctuate during the normal (4-5 d) rat estrous cycle.

We have previously shown that the density of dendritic spines on hippocampal CA1 pyramidal cells is dependent on circulating estradiol and progesterone and fluctuates naturally during the 5 day estrous cycle in the adult rat. To date, however, no detailed characterization of the roles that these hormones play in regulation of spine density has been made. In order to determine the time courses and extent of the effects of estradiol and progesterone on dendritic spine density, we have analyzed the density of dendritic spines on the lateral branches of the apical dendritic tree of Golgi-impregnated CA1 hippocampal pyramidal cells in several experiments. In summary, our findings included the following: (1) Following ovariectomy, circulating estradiol is undetectable within 24 hours; however, spine density decreases gradually over a 6 day period. (2) Spine density does not decrease any further up to 40 days following ovariectomy. (3) Treatment with estradiol alone can reverse the ovariectomy-induced decrease in spine density. (4) Spine density begins to increase within 24 hours following estradiol benzoate injection in an ovariectomized animal, peaks at 2 and 3 days, then gradually decreases over the next 7 day period. (5) Although free estradiol is metabolized more rapidly than estradiol benzoate, there is no difference in the rate of decrease in spine density following injection of either form. (6) Progesterone has a biphasic effect on spine density in that progesterone treatment following estradiol initially increases spine density for a period of 2 to 6 hours but then results in a much sharper decrease than is observed following estradiol alone. By 18 hours following progesterone treatment, spine density is decreased nearly to 6 day ovariectomy values. (7) Treatment of intact rats with the progesterone receptor antagonist, RU 486, during the proestrus phase of the estrous cycle inhibits the proestrus to estrus drop in spine density. These findings account for both the gradual increase and rapid decrease in spine density which we have previously observed during the estrous cycle and indicate that progesterone in particular may be an important factor in the regulation of rapid morphologic changes which occur naturally in the adult brain.