[Frontiers in Bioscience 2, d88-125, March 1, 1997]

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Bianca Marchetti

Department of Pharmacology, Medical School, University of Catania, 95125 Catania, Laboratory of Biotech. Neuropharmacology, OASI Institute for Research and Care (IRCCS) on Mental Retardation and Brain Aging (IRCCS) Troina, (EN), Italy.

Received 8/2/96; Accepted 2/20/97; On-line 3/1/97

4. Hormones as Mediators of Neuron-Glia Plasticity

4.1. Sex Steroids

The role of the sex steroid milieu in glial microenvironment, has been established especially by the work of Garcia-Segura et al., and other investigators (see 97-106), demonstrating that the steroid background is crucial in inducing morphological as well as functional changes of the astroglial cell compartment.

In response to estrogens, astrocytes appear to participate in the remodeling of synaptic contacts on hypothalamic neurons that control the release of pituitary secretions in rodents and primates (99-103). This work is substantiated by the findings indicating that the morphology, immunoreactivity, enzymatic activity, and gene expression of astroglia are sexually dimorphic in several brain areas and/or are modified by different in vivo/in vitro experimental manipulations. Glial cells have been shown to harbor receptors for estradiol and progesterone (102, 105, 106), and estradiol is able to induce the appearance of progesterone receptors. In particular, oligodendrocytes, are known to be capable of synthesizing steroids such as pregnenolone and progesterone, and evidences have been presented for the presence of receptors for these hormones on cultured cells (104-106). Astrocytes were found to possess very few progesterone receptors (PRs); confined to cells derived from female animals (105). In contrast, oligodendrocytes prepared from both male and female animals possessed PRs and, although more abundant in culture from females, receptors in cells from both sexes were increased by exposure to estrogens (105). Estradiol has been shown to induce coordinated modifications in the extension of glial and neuronal processes in the arcuate nucleus of the hypothalamus. This hormonal effect results in natural fluctuations in the ensheathing of the arcuate neurons by glial processes and these glial changes are linked to a remodeling of inhibitory GABAergic synapses during the estrous cycle (see 97, 98). Hormonally induced glial and synaptic changes appear to be dependent on specific recognition or adhesion molecules on the neural and/or glial membranes (see 103). Interestingly enough, the effect of estrogen on astroglial cells has been shown to vary according to the specific CNS region (Fig. 4). Taken together, this information coupled with the finding that astroglial IGF-I-like immune reactivity is affected by the neonatal sex steroid background (99, 107), reinforce the authors view that IGF-I is involved in the hypothalamic control of sexual maturation and in the regulation of neuroendocrine events in adult rats (107, 108).

Figure 4. Regional differences in estrogenic sensitivity of astroglial cells. Primary cultures of astroglial cells were prepared from different brain regions including the hypothalamus, olfactory bulbs, cortex and striatum (43). The effect of estradiol was tested during maturation and differentiation in vitro. Astroglial cell proliferation was determined by the incorporation of [3H]thymidine and results depict a dose-response curve of estradiol 17ß (E2, 10-11 - 10-8 M) on 12 DIV primary rat astrocytes. Note the marked stimulation of DNA labeling in hypothalamic and olfactory bulb astroglia compared to cortical and striatum glia.

4.2. Adrenal corticosteroids

There is abundant evidence that cultured glia possess corticosteroid receptors. Adrenal steroids activate two classes of intracellular receptors, the mineralcorticoid (MR) or type I receptor, and the glucocorticoid (GR) or type II receptor (109). These receptor classes can be distinguished on the basis that the MR displays a higher affinity for corticosterone than does the GR, which preferentially binds synthetic glucocorticoids such as dexamethasone (109). Ligand binding studies have demonstrated the presence of a single population of GRs in both astrocytes and oligodendrocytes (110-112).

Glucocorticoids are known to modulate the expression of a variety of glial proteins, including GFAP, glutamine synthetase (GS), myelin basic protein (MBP), and glycerol phosphate dehydrogenase (110, 113). Low levels of GR mRNA have been detected in white matter cells (114). Using an in vitro model of developing neonatal rat glial cell, we studied developmental expression of GR as a function of time in culture and showed low levels of GR mRNA expressed at 8 days in vitro (DIV) with a progressive increase between 12 and 20 DIV and a plateau reaching thereafter, with the mRNA remaining elevated up to 50 DIV (115). "Young" astroglia respond to dexamethazone with a strong morphologic effect. Astrocytes assume a stellate shape and extend processes (Fig. 5, 115). In the intact brain, glial cells have been shown to respond to glucocorticoids. Adrenalectomy results in increased myelination, while glucocorticoid administration inhibits myelination (see 114, for review), the genesis of oligodendrocytes, and the expression of GFAP (112, 113).

Figure 5. Effect of dexamethazone on the morphologic appearance of rat astroglial cells. Type II astrocytes were cultured as described and the effect of the synthetic glucocorticoid, dexamethazone (DEX, 10-9M) was evaluated after incubation for 24 hr during the differentiation of astroglial cells. A. 12 day-old type II astrocytes stained with the MoAb to GFAP; B. Effect of 24 hr incubation with Dex. Note the stellate appearance and processes extension of astrocytes under glucocorticoid treatment.