Neurosteroidogenesis in Astrocytes, Oligodendrocytes, and Neurons of Cerebral Cortex of Rat Brain

Abstract

The brain is a steroidogenic organ that expresses steroidogenic enzymes and produces neurosteroids. Although considerable information is now available regarding the steroidogenic capacity of the brain, little is known regarding the steroidogenic pathway and relative contributions of astrocytes, oligodendrocytes, and neurons to neurosteroidogenesis. In the present study, we investigated differential gene expression of the key steroidogenic enzymes using RT-PCR and quantitatively evaluated the production of neurosteroids by highly purified astrocytes, oligodendrocytes, and neurons from the cerebral cortex of neonatal rat brains using specific and sensitive RIAs. Astrocytes appear to be the most active steroidogenic cells in the brain. These cells express cytochrome P450 side-chain cleavage (P450scc), 17alpha-hydroxylase/C17-20-lyase (P450c17), 3beta-hydroxysteroid dehydrogenase (3betaHSD), 17beta-hydroxysteroid dehydrogenase (17betaHSD), and cytochrome P450 aromatase (P450arom) and produce pregnenolone (P5), progesterone (P4), dehydroepiandrosterone (DHEA), androstenedione (A4), testosterone (T), estradiol, and estrone. Oligodendrocytes express only P450scc and 3betaHSD and produce P5, P4, and A4. These cells do not express P450c17, 17betaHSD, or P450arom or produce DHEA, T, or estrogen. Neurons express P450scc, P450c17, 3betaHSD, and P450arom and produce P5, DHEA, A4, and estrogen, but do not express 17betaHSD or produce T. By comparing the ability of each cell type in the production of neurosteroids, astrocytes are the major producer of P4, DHEA, and androgens, whereas oligodendrocytes are predominantly the producer of P5 and neurons of estrogens. These findings serve to define the neurosteroidogenic pathway, with special emphasis on the dominant role of astrocytes and their interaction with oligodendrocytes and neurons in the genesis of DHEA and active sex steroids. Thus, we propose that neurosteroidogenesis is accomplished by a tripartite contribution of the three cell types in the brain.

Neurogenin 3 mediates sex chromosome effects on the generation of sex differences in hypothalamic neuronal development

“…Therefore, based on these previous studies and on our present findings, it may be postulated that female neurons are programmed by sex chromosomes for a faster development than male neurons. However, fetal testosterone, after its intracerebral conversion to estradiol (Naftolin et al, 1972; Zwain and Yen, 1999; Hojo et al, 2004), would reprogram male hypothalamic neurons for an enhanced neuronal differentiation. In this regard, it is interesting to note that in cultures from ventromedial hypothalamus of rat fetuses at E16, only neurons from males respond with increased axonal growth to the addition of estradiol to the culture medium (Cambiasso et al, 1995, 2000).…”

Regulation of astroglia by gonadal steroid hormones under physiological and pathological conditions

“…In addition to these hormonal actions, gonadal steroids exert trophic effects on neural cells, which contribute to the maintenance of neural tissue homeostasis, to the regulation of synaptic plasticity and synaptic function; as well as to promoting neuronal survival and neural repair under pathological conditions (see (Arevalo et al, 2015;Guennoun et al, 2015;Sohrabji, 2015;Vest and Pike, 2013) for recent reviews). Sex steroids are also synthesized in other tissues including the nervous tissue, which brought the important idea of considering the CNS as a steroidogenic tissue (do Rego and Vaudry, 2015;Sinchak et al, 2003;Zwain and Yen, 1999).…”

A Unique TGFB1-Driven Genomic Program Links Astrocytosis, Low-Grade Inflammation and Partial Demyelination in Periplaques of Spinal Cords from Progressive Multiple Sclerosis Patients

“…As androgens are known to prevent astrocytosis [29][30][31][32][33][34], our results raise the possibility that in males and females suffering from progressive forms of MS, activation of the AR is somehow defective and fails to downregulate a large set of progliotic genes induced by the TGFB/SMAD1/SMAD2 pathway. This could be due to an age-related decrease of circulating testosterone or of the circulating androgen precursors (Dehydroepiandrosterone and Androstendiol) that can be intracellularly metabolized into testosterone [54][55][56][57]. Another explanation, not exclusive from the former one, could be that the AR signaling pathway might be hampered or disrupted in periplaque astrocytes despite a normal level of circulating or intracrine testosterone.…”