An astroglial basis of major depressive disorder? An overview

Abstract

Depression is a chronic, recurring, and serious mood disorder that afflicts up to 20% of the global population. The monoamine hypothesis has dominated our understanding of the pharmacotherapy of depression for more than half a century; however, our understanding of the pathophysiology and pathogenesis of major depression has lagged far behind. Astrocytes are the most abundant and versatile cells in the brain, participating in most, if not all, of brain functions as both a passive housekeeper and an active player. Mounting evidence from clinical, preclinical and post-mortem studies has revealed a decrease in the number or density of astrocytes and morphological and functional astroglial atrophy in patients with major depressive disorder (MDD) and in animal models of depression. Furthermore, currently available antidepressant treatments at least partially exert their therapeutic effects on astrocytes. More importantly, dysfunctional astrocytes lead to depressive-like phenotypes in animals. Together, current studies point to astroglial pathology as the potential root cause of MDD. Thus, a shift from a neuron-centric to an astrocyte-centric cause of MDD has gained increasing attention during the past two decades. Here we will summarize the current evidence supporting the hypothesis that MDD is a disease of astrocyte pathology and highlight previous studies on promising strategies that directly target astrocytes for the development of novel antidepressant treatments.

N-3 polyunsaturated fatty acids promote astrocyte differentiation and neurotrophin production independent of cAMP in patient-derived neural stem cells

“…Decrease in astrocyte count and GFAP expression are seen at many brain regions in MDD post-mortem studies [32–35] and animal models of depression [8]. A recent reprot suggested that antidepressants could induce recovery of astrocytes in MDD, which could be a potential mechanism for their anti-depression effect [8]. To test whether n-3 PUFAs affect astrocyte formation, we observed the effect of n-3 PUFAs on astrocyte differentiation from iNSCs derived from SSRI-sensitive or -resistant MDD subjects.…”

“…Decrease in astrocyte count and GFAP expression are often seen in MDD post-mortem studies [32, 33] [34, 35] [50]. Astrocyte reduction was also observed in a variety of animal models of depression [8]. Antidepressants, including SSRIs, could increase/restore the astrocyte counts or GFAP staining, which positively correlated with attenuated “depression-indicators” in rodents [8].…”

“…Brain regions and even cell-types contributing to MDD are not well established [4]. Evidence from clinical, preclinical and post-mortem studies suggests that dysfunction and degeneration of astrocytes may be one of potential candidates, and astrocytes may also represent a potential therapeutic target for MDD [5–8]. Antidepressants, including SSRIs and ketamine, increase brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) expression in primary cultured animal astrocytes [9–11].…”

“…Antidepressants, including SSRIs and ketamine, increase brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) expression in primary cultured animal astrocytes [9–11]. Substantial evidence suggested that astrocytes might be the main resource of antidepressant-induced BDNF [8]. Furthermore, overexpression of BDNF in astrocytes leads to antidepressant-like activity in mice [12].…”

Regionally selective knockdown of astroglial glutamate transporters in infralimbic cortex induces a depressive phenotype in mice

“…Astrocytes play a major role in excitatory neurotransmission by controlling the glutamate–glutamine cycle, which is fundamental for the synaptic plasticity associated with cognitive processes (Araque & Perea, ; Oliveira, Krügel, Köles, Illes, & Wirkner, ; Perea & Araque, ; Perea, Sur, & Araque, ). Moreover, they have been proposed as an early contributor to the underlying pathogenesis of MDD (Haroon, Miller, & Sanacora, ; Liu, Teschemacher, & Kasparov, ; Sanacora & Banasr, ; Wang, Jie, Liu, Yang, & Gao, ). Reductions of astrocyte number and alterations of astroglial function in frontolimbic structures have been found in MDD patients and suicide victims (Banasr & Duman, ; Peng, Verkhratsky, Gu, & Li, ; Rajkowska & Stockmeier, ).…”