PARENT SESSION
MINISYMPOSIUM VII: New Insights on the Role of Estrogens in the Brain
Tuesday, July 31, 2001, 10:30 AM-12:00 PM
Westin-Confederation II
Chair: Darrell W. Brann
Speakers: Darrell W Brann, Margaret M McCarthy, Frederick Naftolin

ESTRADIOL MEDIATES SEXUALLY DIMORPHIC ASTROCYTE AND NEURONAL MORPHOLOGY VIA MULTIPLE MECHANISMS.

McCarthy, Margaret¹, Mong, Jessica², Amateau, Stuart¹, ^{1 2}

ABSTRACT- Astrocytes in the preoptic area and arcuate nucleus of the rat exhibit a sexually dimorphic morphology as early as the day of birth that persists into adulthood. This dimorphism is hormonally dependent and a function of estradiol that is derived from the aromatization in neurons of testicular- testosterone (Mong and McCarthy, 1999, J. Neurobiol. 40: 602; Amateau, Mong and McCarthy 2000, Soc. Neurosci. Abst. 224.33). As a result, the astrocytes of males exhibit a higher degree of complexity as evidenced by increased numbers, branching and length of cellular processes. The greater stellation of astrocytes in males is correlated with decreased numbers of axospinous synapses in the arcuate nucleus (Mong et al., 2001, J.Comp. Neurol., 432:259). These two morphologies may be functionally related based on extrapolation from data in the adult in which increased astrocyte process extension is found to decrease synapses (Garcia-Segura et al., 1999, J Neurobiol. 40:489). A central question is the mechanism of estradiol-induced astrocyte differentiation. We have failed to detect estrogen receptors in astrocytes of the arcuate nucleus using double-labeled fluorescent immunocytochemistry. This suggests that neurons may be the primary target of estradiol action and subsequently trandsduce the signal to the astrocytes. We have previously found GABA levels to be significantly higher in the arcuate nucleus of newborn males compared to females (Davis et al., 1999; Neuroscience 90: 1471). GABA is made exclusively in neurons by the rate limiting enzyme, glutamic acid decarboxylase (GAD). Steroid-induced differentiation of astrocytes in the arcuate nucleus was prevented by decreasing the synthesis of GABA with antisense oligonucleotides directed against GAD mRNA. Conversely, astrocyte differentiation was induced in the absence of estradiol by exogenous administration of a GABA agonist. These data suggest that estradiol acts in neurons of the arcuate nucleus to increase the synthesis of GABA which is released into the extracellular space and acts on astrocytes to induce their differentiation (Mong, Nunez and McCarthy, 2001, submitted). Alternatively, in the developing preoptic area estradiol increases the number of dendritic spines and preliminary evidence suggests this occurs via increased synthesis and release of prostaglandin E2 (PGE₂) from astrocytes. Perinatal preoptic area neurons cocultured with astrocytes respond to exogenous estradiol or PGE₂ with an increase in spine density of equal magnitude. However, coadministration of the prostaglandin synthesis inhibitor, indomethacin, blocks the induction of spines by estradiol but not PGE₂. This suggests that estradiol increases PGE₂ synthesis and that this endogenous PGE₂ serves as the mediator of estradiols downstream effects on synapse density. Therefore in this brain area, increased astrocyte differentiation and the induction of synapses appear to be positively, rather than negatively, correlated as they are in the arcuate nucleus. Taken together, these findings illustrate the complex relationship between estradiol, astrocytes and neurons and emphasize the importance of regionally specific and developmentally

KEY WORDS: astrocytes, estrogen, brain development, hypothalamus