Astrocytes are a neural target of morphine action via glucocorticoid receptor‐dependent signaling

Abstract

Chronic opioid use leads to the structural reorganization of neuronal networks, involving genetic reprogramming in neurons and glial cells. Our previous in vivo studies have revealed that a significant fraction of the morphine-induced alterations to the striatal transcriptome included glucocorticoid (GC) receptor (GR)-dependent genes. Additional analyses suggested glial cells to be the locus of these changes. In the current study, we aimed to differentiate the direct transcriptional effects of morphine and a GR agonist on primary striatal neurons and astrocytes. Whole-genome transcriptional profiling revealed that while morphine had no significant effect on gene expression in both cell types, dexamethasone significantly altered the transcriptional profile in astrocytes but not neurons. We obtained a complete dataset of genes undergoing the regulation, which includes genes related to glucose metabolism (Pdk4), circadian activity (Per1) and cell differentiation (Sox2). There was also an overlap between morphine-induced transcripts in striatum and GR-dependent transcripts in cultured astrocytes. We further analyzed the regulation of expression of one gene belonging to both groups, serum and GC regulated kinase 1 (Sgk1). We identified two transcriptional variants of Sgk1 that displayed selective GR-dependent upregulation in cultured astrocytes but not neurons. Moreover, these variants were the only two that were found to be upregulated in vivo by morphine in a GR-dependent fashion. Our data suggest that the morphine-induced, GR-dependent component of transcriptome alterations in the striatum is confined to astrocytes. Identification of this mechanism opens new directions for research on the role of astrocytes in the central effects of opioids. V V C 2013 Wiley Periodicals, Inc.

Regulation of alternative gene transcription in the striatum in response to antidepressant drugs

“…Our analyzes indicated that these systems depend on different molecular mechanisms that either predominantly use gene proximal promoters (employing SRF and CREB1 factors) or enhancer regions (GR). Moreover, it has been previously shown that these two transcriptional systems are active in different cellular compartments of the brain (Carter et al, 2012;Korostynski et al, 2013;Slezak et al, 2013). The comparison of transcriptional response to pharmacological stimuli between neurons and glia provides novel insight into the synergy in control of brain plasticity between these two compartments (Cadet and Bisagno, 2014).…”

“…Our results also suggest potential involvement of the transcriptional insulators, such as CTCF, in the genomic localization of GR-dependent and antidepressant-induced transcriptional alterations in the brain (Ishihara et al, 2006). The induction of a GR-regulated expression pattern in the striatum is common not only for tranylcypromine and mianserin but also for fluoxetine, tianeptine and bupropion (Korostynski et al, 2013). It has been suggested that the general physiological response of glial cells is involved in the therapeutic effect of antidepressants (Sanacora and Banasr, 2013).…”

“…Nevertheless, the genetic elements and pathways that control the selection of an active transcription initiation or termination are not entirely understood (Davuluri et al, 2008). Multiple studies have attempted to profile the effects of antidepressants using highthroughput gene expression arrays (Bohm et al, 2006;Conti et al, 2007;Korostynski et al, 2013;Landgrebe et al, 2002;Malki et al, 2012;Patricio et al, 2014). However, the previous findings were not entirely conclusive, and more complementary knowledge of antidepressant-regulated genes in the brain is required.…”

“…Genes from this cluster are functionally associated with the control of cell physiology and metabolism, including involved in lipid metabolism Plin4 (Wolins et al, 2005), the glucose transporter Slc2a1 (Masters et al, 1991) and several components of the Golgi apparatus (Gaudet et al, 2013). Recently, accumulating lines of evidence have indicated that astrocytes and microglia are the major cellular components of M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT Piechota et al, 2014 17 glucocorticoid-dependent transcription in the nervous system (Carter et al, 2012;Jenkins et al, 2014;Slezak et al, 2013). To obtain a comprehensive view of this molecular system, we stimulated primary cultures of astroglia with the GR agonist dexamethasone.…”

Identifying the Cellular Targets of Drug Action in the Central Nervous System Following Corticosteroid Therapy

“…25 While neurons engage in cross-talk with oligodendroglial cells during myelination, one study has reported limited CS effects in striatal neurons, suggesting that at least some neurons are not direct targets of CS action. 26 Such observations suggest that CS may impact myelination through indirect effects mediated by nonmyelinogenic glial cell intermediaries, but rigorous evaluation of direct effects of CS on oligodendroglia is lacking. There is heavy reliance in the field on histological observations in cultures, but the constituent cell types are often poorly characterized.…”