Dysfunctional serotonergic neuron-astrocyte signaling in depressive-like states

Abstract

Astrocytes play crucial roles in brain homeostasis and are regulatory elements of neuronal and synaptic physiology. Astrocytic alterations have been found in Major Depressive Disorder (MDD) patients; however, the consequences of astrocyte Ca2+ signaling in MDD are poorly understood. Here, we found that corticosterone-treated juvenile mice (Cort-mice) showed altered astrocytic Ca2+ dynamics in mPFC both in resting conditions and during social interactions, in line with altered mice behavior. Additionally, Cort-mice displayed reduced serotonin (5-HT)-mediated Ca2+ signaling in mPFC astrocytes, and aberrant 5-HT-driven synaptic plasticity in layer 2/3 mPFC neurons. Downregulation of astrocyte Ca2+ signaling in naïve animals mimicked the synaptic deficits found in Cort-mice. Remarkably, boosting astrocyte Ca2+ signaling with Gq-DREADDS restored to the control levels mood and cognitive abilities in Cort-mice. This study highlights the important role of astrocyte Ca2+ signaling for homeostatic control of brain circuits and behavior, but also reveals its potential therapeutic value for depressive-like states.

Ketamine modulates a norepinephrine-astroglial circuit to persistently suppress futility-induced passivity

“…Ketamine has been shown to drive monoaminergic signaling to elevate NE and 5-HT in the extracellular space 16,62 , and, in the case of serotonin 74 , this elevation has been shown to be important to mediate antidepressant-like effects of ketamine in rodents. Astrocytes have been shown to respond to elevations in NE 21–24,38 and serotonin 31 with elevations in cytosolic calcium. Furthermore, astroglial responsiveness to serotonin has recently been shown to be disrupted in rodent depression models, and stimulating prefrontal cortex astrocytes chemogenetically has been shown to rescue depression-related behavioral phenotypes 31 .…”

“…Astrocytes have been shown to respond to elevations in NE 21–24,38 and serotonin 31 with elevations in cytosolic calcium. Furthermore, astroglial responsiveness to serotonin has recently been shown to be disrupted in rodent depression models, and stimulating prefrontal cortex astrocytes chemogenetically has been shown to rescue depression-related behavioral phenotypes 31 . Ketamine has also been shown in vitro to decrease astroglial calcium responses to stimuli like ATP and to attenuate calcium-coupled secretion of chemical messengers by astroglia 75 .…”

“…Recently, astroglia, a class of non-neuronal cells that play important roles in modulating neural activity 20–26 , has been implicated in the etiology of MDD 27,28 . Post-mortem anatomical analysis of MDD patient brains indicate that depression is associated with decreased astrocyte density in the hippocampus 29 and cortex 30 , and in a corticosterone-induced rodent model of depression-like state, cortical astrocytes exhibited abnormal behavior-and serotonin-triggered responses 31 . Additionally, disruption to astroglial purinergic signaling contributes to depression-like phenotypes in rodents, and supplementing ATP chronically, or blocking acute ATP/adenosine signaling, leads to antidepressant-like effects 32–34 .…”

Role of Glial Cells in Depression and Drug Addiction

“…More recently, revelation of the importance of astrocyte Ca 2+ signaling in homeostatic control of brain circuits and behavior has led to the suggestion of potential exploitation of this system in MDD treatment [179] [180]. Further understanding of astrocyte-neuron involvement in MDD pathology including the alterations of mid-spiny neurons and pyramidal neurons, as well as the alterations of gliotransmitters between astrocytes and neurons could provide novel targets in MDD [181].…”

Astroglial Dysfunctions in Mood Disorders and Rodent Stress Models: Consequences on Behavior and Potential as Treatment Target

“…Note that, in this study, we showed no effect of the GFAP cell ablation or activation on anxiety-like behaviors, which may oppose the findings previously discussed, where optogenetics or acute chemogenetics were employed. A concomitant recent study by González-Arias et al [ 188 ] investigated PFC GFAP+ cell activity in juvenile mice subjected to chronic corticosterone treatment and showed impairments of astroglial activity during tests measuring anxiety or social interaction deficits that were reversed in mice by chronic chemogenetic enhancement of GFAP+ cell activity. Another study used chronic chemogenetic activation to investigate astroglial modulation of alcohol consumption [ 189 ].…”