Steroid mediated astrocyte differentiation in the developing hypothalamus: Implications for sexually dimorphic synaptic patterning

Abstract

The developing rodent brain is exquisitely sensitive to estrogens which permanently differentiate the neural substrates during a restricted developmental period. One of the more striking sexual dimorphisms in the adult brain is the synaptic patterning in the arcuate nucleus (ARC) of the hypothalamus where males have twice the number of axosomatic and half the number of axodendritic spine synapses as females. Early exposure to estrogens dictate the adult dimorphism but the exact timing, mechanism, and site of steroid action, remain unknown. Astrocytes also exhibit sexual dimorphisms in adulthood and their role in mediating neuronal morphology is becoming increasingly evident. We have demonstrated that astrocytes in the neonatal ARC exhibit a sexually dimorphic morphology as a result of differential exposure to estrogens. Conflicting reports have left the site of steroid-mediated astrocyte responsiveness in the ARC unresolved and a lack of evidence for estrogen receptors (ER) in ARC astrocytes suggests estrogen induces a modulatory favor in neighboring ER containing neurons, which alters astrocyte morphology. Here we report that in vivo reduction of GABA synthesis in the neonatal rat brain by antisense oligodeoxynucleotides prevented estrogen-induced astrocyte differentiation whereas enhancement of endogenous GABA activity with a benzodiazepine increased differentiation in the absence of estrogen. Given that GABA is made only in neurons and its synthesis is increased by estrogen. Given that GABA is made only in neurons and its synthesis is increased by estrogen, we conclude that it is acting as a diffusable factor inducing the differentiation of neighboring astrocytes. Coincident with the steroid-induced increase in astrocyte differentiation is a reduction of dendritic spines and consequently fewer axospinous synapses in males than females. In the immediately adjacent ventromedial nucleus, neonatal astrocytes are immature and unresponsive to steroids. Neurons in this region show no change in dendritic spines in the first few days of life but do exhibit increased dendritic branching as a result of testosterone exposure. These finding illustrate the importance of distinct populations of astrocytes in restricted brain regions and their potential importance to the establishment of regionally specific synaptic patterning.