Differential regulation of neuregulin 1 expression by progesterone in astrocytes and neurons

Abstract

Glial2neuronal interactions are crucial processes in neuromodulation and synaptic plasticity. The neuregulin 1 family of growth and differentiation factors have been implicated as bidirectional signaling molecules that are involved in mediating some of these interactions. We have shown previously that neuregulin 1 expression is regulated by the gonadal hormones progesterone and 17b-estradiol in the CNS, which might represent a novel, indirect mechanism of the neuromodulatory actions of these gonadal hormones. In the present study, we sought to determine the effects of progesterone and 17b-estradiol on neuregulin 1 expression in rat cortical astrocytes and neurons in vitro. We observed that progesterone increased the expression of neuregulin 1 mRNA and protein in a dose-dependent manner in cultured astrocytes, which was blocked by the progesterone receptor antagonist RU-486. In contrast, 17b-estradiol did not increase either neuregulin 1 mRNA or protein in astrocytes. We observed no effect of either progesterone or 17b-estradiol on neuregulin 1 mRNA and protein in rat cortical neurons in vitro. Finally, we observed that treatment of cortical neurons with recombinant NRG1-b1 caused PSD-95 to localize in puncta similar to that observed following treatment with astrocyte-conditioned medium. These results demonstrate that progesterone regulates neuregulin 1 expression, principally in astrocytes. This might represent a novel mechanism of progesterone-mediated modulation of neurotransmission through the regulation of astrocyte-derived neuregulin 1.Keywords: Sex hormones, neuregulin, glial activation, PSD-95, NGR1 INTRODUCTIONThe hallmark of pathological pain is sensitization of synaptic neurotransmission in the CNS. Previously, this has been attributed to aberrant neuronal activity that involved only neurons of the nociceptive axis in the CNS. However, there is increasing evidence that glial cells have a key role in modulating neuronal processes in the normal and diseased CNS. In particular, glial cells are such active participants in synaptic transmission (Parpura et al., 1994;Pfrieger and Barres, 1997;Araque et al., 2000;Ullian et al., 2001) that the functional unit of neurotransmission should now be considered to include both neuronal and glial components (De Leo et al., 2006). This is particularly true in the case of chronic pain states where glial cells are intimately involved (Garrison et al., 1994;Colburn et al., 1997;DeLeo and Yezierski, 2001;Watkins et al., 2001).The steroid hormones that are produced primarily by the gonads (i.e. 17b-estradiol, progesterone and testosterone) and their metabolites have profound neuromodulatory activities in the CNS. In the case of nociception, it has been demonstrated that manipulation of hormone levels by removing the gonads alters both basal nociceptive sensitivity and the manifestation of pain-like behaviors in several rodent models of nerve injury (Jordan, 1999;Fillingim and Ness, 2000;Craft et al., 2004). Although general observations about gonadal steroids can be made, t...

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