Astroglial Serotonin Receptors as the Central Target of Classic Antidepressants

Abstract

Major depressive disorder (MDD) presents multiple clinical phenotypes and has complex underlying pathological mechanisms. Existing theories cannot completely explain the pathophysiological mechanism(s) of MDD, while the pharmacology of current antidepressants is far from being fully understood. Astrocytes, the homeostatic and defensive cells of the central nervous system, contribute to shaping behaviors, and regulating mood and emotions. A detailed introduction on the role of astrocytes in depressive disorders is thus required, to which this chapter is dedicated. We also focus on the interactions between classic antidepressants and serotonin receptors, overview the role of astrocytes in the pharmacological mechanisms of various antidepressants, and present astrocytes as targets for the treatment of bipolar disorder. We provide a foundation of knowledge on the role of astrocytes in depressive disorders and astroglial 5-HT_2B receptors as targets for selective serotonin reuptake inhibitors in vivo and in vitro.

Keywords: 5-HT2B receptors; Astrocytes; Fluoxetine; Major depressive disorder; Selective serotonin reuptake inhibitors.

Fig. 1

Schematic illustration of biphasic concentration-dependent regulation of Cav-1 gene expression and GSK-3β activity by fluoxetine in astrocytes. Fluoxetine is an agonist to serotonin 2B receptors (5-HT_2BR). Acute treatment with fluoxetine at low concentrations (green arrows) stimulates Src which phosphorylates epidermal growth factor (EGF) receptors (EGFR) at Y845 residue and in turn activates phosphoinositide 3 kinase (PI3K)-AKT signaling pathway. The AKT phosphorylation by fluoxetine at low concentrations inhibits c-Fos gene expression and subsequently decreases caveolin-1 (Cav-1) gene expression (chronic effects) that in turn decreases membrane content of PTEN (phosphatase and tensin homolog), induces phosphorylation and stimulation of PI3K, and elevates glycogen synthase kinase 3 (GSK-3β) phosphorylation thus suppressing its activity. At higher concentrations, fluoxetine (red arrows) stimulates metalloproteinase (MMP) and induces shedding of growth factor which stimulates EGFR and activates mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinases 1/2 (ERK1/2) signal pathway. The ERK1/2 phosphorylation by fluoxetine at high concentrations stimulates cFos gene expression and subsequently increases Cav-1 gene expression (chronic effects), which acts on PTEN/PI3K/AKT/GSK-3β in an inverse fashion. (From Li et al. 2017)

Fig. 2

Treatment with chronic stress enhances neuronal apoptosis triggered by overload with iron. Mice were pretreated without or with chronic unpredictable mild stress (CUMS) for 6 weeks; in week 6, animals were randomly separated to be injected with dextran (CUMS group) or iron dextran (CUMS+Iron group) for 6 days. Apoptosis was detected by TUNEL assay in the cortex (a) and hippocampus (c), where neuronal nuclei were stained with NeuN (red), while all the cell nuclei were labeled with DAPI (blue in merge). Percentage of cell death was determined by the ratio of TUNEL+ and NeuN+ cells, with the cortical and hippocampal regions analyzed in (b, d), respectively. Data are presented as mean ± SEM, n = 6. *p < 0.05, statistically significant difference compared with control, untreated group; **p < 0.05, statistically significant difference compared with any other group. (From Liang et al. 2020)

Fig. 3

P2X₇ receptors mediate the selective decrease of 5-HT_2B receptors in astrocytes treated with chronic sleep deprivation. (a) Immunolabelled 5-HT_2B receptors (green) were co-stained with glial fibrillary acidic protein (GFAP, red) and NeuN (blue) in the mice frontal cortex treated with sham (Control) or exposed to sleep deprivation for 3 weeks of wild-type (WT) and P2X₇ receptor knockout (P2X₇R-KO) mice. Scale bar, 20μm. (b) 5-HT_2B receptors immunolabeling intensity of neurones and astrocytes, respectively, relative to the cell-free parenchyma in the cortex, normalized to the intensity of a matching sham group. (c) RT-PCR analysis of 5-HT_2B receptors mRNA expression in WT or P2X₇R-KO mice treated with sleep deprivation for 3 weeks, expressed as the relative expression ratio of 5-HT_2B receptor/GAPDH, the latter used as loading control. Data represent mean ± SEM. *Indicates statistically significant (p < 0.05) difference from matching sham groups, n = 6. (From Xia et al. 2020)