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Introduction: Astroglia represent the main cellular homeostatic system of the central nervous system (CNS). Astrocytes are intimately involved in regulation and maintenance of neurotransmission by regulating neurotransmitters removal and turnover and by supplying neurons with neurotransmitters precursors. Astroglial cells are fundamental elements of monoaminergic transmission in the brain and in the spinal cord. Astrocytes receive monoaminergic inputs and control catabolism of monoamines through dedicated transporters and intracellular enzymatic pathways. Areas covered: Astroglial cells express serotonergic receptors; in this review, we provide an in-depth characterization of 5-HT2B receptors. Activation of these receptors triggers numerous intracellular signaling cascades that regulate expression of multiple genes. Astroglial 5-HT2B receptors are activated by serotonin-specific reuptake inhibitors, such as major anti-depressant fluoxetine. Expression of astroglial serotonin receptors undergoes remarkable changes in depression disorders, and these changes can be corrected by chronic treatment with anti-depressant drugs. Expert commentary: Depressive behaviors, which occur in rodents following chronic stress or in neurotoxic models of Parkinson disease, are associated with significant changes in the expression of astroglial, but not neuronal 5-HT2B receptors; while therapy with anti-depressants normalizes both receptors expression and depressive behavioral phenotype. In summary, astroglial serotonin receptors are linked to mood disorders and may represent a novel target for cell- and molecule-specific therapies of depression and mood disorders. [ABSTRACT FROM AUTHOR]

Abstract: We have recently shown that freshly isolated astrocytes from the mouse brain express mRNA for the L-channel gene Cav1.3 to at least the same degree (per mg mRNA) as corresponding neurons. The amount of extracellular Ca2+ actually entering cultured astrocytes by its opening is modest, but due to secondary Ca2+-mediated stimulation of the ryanodine receptor (RyR) the increase in free cytosolic Ca2+ [Ca2+]i is substantial. The other Cav1 subtype expressed in brain is Cav1.2, which is even expressed in higher density. Although the different primers used for the two genes preclude exact quantitative comparison, the present study suggests that this is also the case in the freshly isolated astrocytes and neurons, which express equal Cav1.2 densities. Again, most of the increase in [Ca2+]i occurred by RyR activity. In contrast to Cav1.3 the expression of Cav1.2 was greatly increased (doubled) after two weeks of treatment with fluoxetine hydrochloride (10mg/kg). Accordingly [Ca2+]i in cultured astrocytes exposed to the addition of 10–60mM KCl increased substantially in cultured astrocytes treated chronically with fluoxetine with the lag time until the effect was observed depending upon the fluoxetine concentration. This effect was inhibited by nifedipine or siRNA against Cav1.2. The increase in K+-induced rise in [Ca2+]i after fluoxetine treatment is directly opposite to a decrease in [Ca2+]i after treatment with any of the anti-bipolar drugs lithium, carbamazepine or valproic acid, due to reduced capacitative Ca2+ influx. We have previously shown a similar effect after fluoxetine treatment, but it becomes overridden by the Cav1.2 up-regulation. [Copyright &y& Elsevier]

Abstract: The importance of Ca2+ signaling in astrocytes is undisputed but a potential role of Ca2+ influx via L-channels in the brain in vivo is disputed, although expression of these channels in cultured astrocytes is recognized. This study shows that an increase in free cytosolic Ca2+ concentration ([Ca2+] i ) in astrocytes in primary cultures in response to an increased extracellular K+ concentration (45mM) is inhibited not only by nifedipine (confirming previous observations) but also to a very large extent by ryanodine, inhibiting ryanodine receptor-mediated release of Ca2+, known to occur in response to an elevation in [Ca2+] i . This means that the actual influx of Ca2+ is modest, which may contribute to the difficulty in demonstrating L-channel-mediated Ca2+ currents in astrocytes in intact brain tissue. Chronic treatment with any of the 3 conventional anti-bipolar drugs lithium, carbamazepine or valproic acid similarly causes a pronounced inhibition of K+-mediated increase in [Ca2+] i . This is shown to be due to an inhibition of capacitative Ca2+ influx, reflected by decreased mRNA and protein expression of the ‘transient receptor potential channel’ (TRPC1), a constituent of store-operated channels (SOCEs). Literature data are cited (i) showing that depolarization-mediated Ca2+ influx in response to an elevated extracellular K+ concentration is important for generation of Ca2+ oscillations and for the stimulatory effect of elevated K+ concentrations in intact, non-cultured brain tissue, and (ii) that Ca2+ channel activity is dependent upon availability of metabolic substrates, including glycogen. Finally, expression of mRNA for Cav1.3 is demonstrated in freshly separated astrocytes from normal brain. [Copyright &y& Elsevier]

Neuronal excitation leads to an increase of the extracellular K concentration ([K]) in brain. This increase has at least two energy-consuming consequences: (1) a depolarization-mediated change in intracellular pH (pH) in astrocytes due to depolarization-mediated increased activity of the acid-extruding Na/bicarbonate transporter NBCe1 (driven by secondary active transport, supported by ion gradients established by the Na, K-ATPase); and (2) activation of cellular reuptake of K mediated by the Na, K-ATPase in both neurons and astrocytes. Astrocytic, but not neuronal increase in NBCe1 activity and pH is also seen after chronic treatment with either of the two anti-bipolar drugs carbamazepine or valproic acid. The third 'classical' anti-bipolar drug, 'lithium' increases astrocytic pH by a different mechanism (stimulation of the acid extruding Na/H exchanger NHE1). The acid extruder fluxes, which depend upon the change in pH per time unit (ΔpH/Δt) and intracellular buffering power, have not been established in most of these situations. Therefore their stimulatory effects on energy metabolism has not been quantitated. This has been done in the present study in cultured mouse astrocytes. pH was determined using the fluorescent pH-sensitive indicator BCECF-AM and an Olympus IX71 live cell imaging fluorescence microscope. Molar acid extrusion fluxes (indicating transporter activity) were determined as pH changes/min during recovery after acid-loading with NH/NH, NBCe1 mRNA and protein expression in the cultured cells by, respectively RT-PCR and Western blotting. Drug-induced up-regulation of acid extrusion flux was slow and less than physiologically seen after increase in K concentration. Energetically, K uptake is much costlier than NBCe1 activity. [ABSTRACT FROM AUTHOR]

Abstract: Primary cultures of mouse astrocytes were used to investigate effects by chronic treatment (3–21 days) with fluoxetine (0.5–10μM) on capacitative Ca2+ influx after treatment with the SERCA inhibitor thapsigargin and on receptor agonist-induced increases in free cytosolic Ca2+ concentration [Ca2+]i, determined with Fura-2. The agonists were the 5-HT2B agonist fluoxetine, the α2-adrenergic agonist dexmedetomidine, and ryanodine receptor (RyR) and IP3 receptor (IP3R) agonists. In untreated sister cultures each agonist distinctly increased [Ca2+]i, but in cultures treated for sufficient length of time or with sufficiently high doses of fluoxetine, acute administration of fluoxetine, dexmedetomidine, or RyR or IP3R agonists elicited reduced, in some cases abolished, effects. Capacitative Ca2+ entry, meditated by TRPC1 channels, was sufficiently inhibited to cause a depletion of Ca2+ stores, which could explain the reduced agonist effects. All effects of chronic fluoxetine administration could be replicated by TRPC1 channel antibody or siRNA. Since increases in astrocytic [Ca2+]i regulate release of gliotransmitters, these effects may have profound effects on brain function. They may be important for therapeutic effects of all 5 conventional ‘serotonin-specific reuptake inhibitors’ (SSRIs), which at concentrations used therapeutically (∼1μM) share other of fluoxetine''s chronic effects (Zhang et al., Neuron Glia Biol. 16 (2010) 1–13). [Copyright &y& Elsevier]

Abstract: We have previously shown that fluoxetine causes ERK1/2 phosphorylation in cultured mouse astrocytes mediated exclusively by stimulation of 5-HT2B receptors (). This raises the question whether this is also the case for serotonin (5-HT) itself. In the present study serotonin was found to induce ERK1/2 phosphorylation by stimulation of 5-HT2B receptors with high affinity (EC50: 20–30pM), and by stimulation of 5-HT2C receptor with low affinity (EC50: 1μM or higher). ERK1/2 phosphorylation induced by stimulation of either 5-HT2B or 5-HT2C receptors was mediated by epidermal growth factor (EGF) receptor transactivation (Peng et al., this issue), shown by the inhibitory effect of AG1478, an inhibitor of the EGF receptor tyrosine kinase, and GM6001, an inhibitor of Zn-dependent metalloproteinases, and thus of 5-HT2B receptor-mediated EGF receptor agonist release. It is discussed that the high potency of the 5-HT2B-mediated effect is consistent with literature data for binding affinity of serotonin to cloned human 5-HT2B receptors and with observations of low extracellular concentrations of serotonin in brain, which would allow a demonstrated moderate and modality-dependent increase in specific brain areas to activate 5-HT2B receptors. In contrast the relevance of the observed 5-HT2C receptors on astrocytes is questioned. [Copyright &y& Elsevier]

Abstract: EGF receptor transactivation has been known for more than ten years. It is a signal pathway in which a G-protein-coupled receptor (GPCR) signal leads to release of a growth factor, which in turn activates the EGF receptor-tyrosine kinase in the same or adjacent cells. Astrocytes express a number of GPCRs and play key roles in brain function. Astrocytic transactivation is of special interest, since its autocrine effect may regulate gene expression and alter cell functions in the cells themselves and its paracrine effect may provide additional opportunities for cross-talk between astrocytes and their neighbors, such as neurons. The signal pathways of EGF transactivation are complicated. This does not only apply to the pathways leading to shedding of growth factor(s), but also to the downstream signal pathways of the EGF receptor, i.e., MAPK and PI3K. The latter may vary according to the type of growth factor released, the sites of tyrosine phosphorylation on the EGF receptor, and the duration of the phosphorylation. Using primary cell cultures we have found that dexmedetomidine, a specific α2-adrenergic receptor, induced shedding of HB-EGF from astrocytes, which in turn transactivated EGF receptors and stimulated astrocytic c-Fos and FosB expression. At the same time released HB-EGF protected neurons from injury caused by H2O2. We have also confirmed dexmedetomidine transactivation in the brain in vivo. EGF transactivation by 5-HT2B receptor stimulation was responsible for up-regulation of cPLA2 in astrocytes by fluoxetine, an antidepressant and inhibitor of the serotonin transporter, which also is a specific 5-HT2B agonist. [Copyright &y& Elsevier]

In well-differentiated primary cultures of mouse astrocytes, which express no serotonin transporter (SERT), the ‘serotonin-specific reuptake inhibitor’ (SSRI) fluoxetine leads acutely to 5-HT2B receptor-mediated, transactivation-dependent phosphorylation of extracellular regulated kinases 1/2 (ERK1/2) with an EC50 of ~5 μM, and chronically to ERK1/2 phosphorylation-dependent upregulation of mRNA and protein expression of calcium-dependent phospholipase A2 (cPLA2) with ten-fold higher affinity. This affinity is high enough that fluoxetine given therapeutically may activate astrocytic 5-HT2B receptors (Li et al., 2008, 2009). We now confirm the expression of 5-HT2B receptors in astrocytes freshly dissociated from mouse brain and isolated by fluorescence-activated cell sorting (FACS) and investigate in cultured cells if the effects of fluoxetine are shared by all five conventional SSRIs with sufficiently high affinity to be relevant for mechanism(s) of action of SSRIs. Phosphorylated and total ERK1/2 and mRNA and protein expression of cPLA2a were determined by Western blot and reverse transcription polymerase chain reaction (RT-PCR). Paroxetine, which differs widely from fluoxetine in affinity for SERT and for another 5-HT2 receptor, the 5-HT2C receptor, acted acutely and chronically like fluoxetine. One micromolar of paroxetine, fluvoxamine or sertraline increased cPLA2a expression during chronic treatment; citalopram had a similar effect at 0.1–0.5 μM; these are therapeutically relevant concentrations. [ABSTRACT FROM PUBLISHER]

Abstract: Our previous work demonstrated dexmedetomidine-activated phosphorylation of extracellular regulated kinases 1 and 2 (ERK1/2) in primary cultures of mouse astrocytes and showed that it is evoked by α2-adrenoceptor-mediated transactivation of epidermal growth factor (EGF) receptors, a known response to activation of Gi/o- or Gq-coupled receptors [Li, B., Du, T., Li, H., Gu, L., Zhang, H., Huang, J., Hertz, L., Peng, L., 2008a. Signaling pathways for transactivation by dexmedetomidine of epidermal growth factor receptors in astrocytes and its paracrine effect on neurons. Br. J. Pharmacol. 154, 191–203]. Like most studies of transactivation, that study used cultured cells, raising the question whether a similar effect can be demonstrated in intact brain tissue and the brain in vivo. In the present study we have shown that (i) dexmedetomidine-mediated ERK1/2 phosphorylation occurs in mouse brain slices with a similar concentration dependence as in cultured astrocytes (near-maximum effect at 50nM); (ii) intraperitoneal injection of dexmedetomidine (3μg/kg) in adult mice causes rapid phosphorylation of the EGF receptor (at Y845 and Y992) and of ERK1/2 in the brain; (iii) both EGF receptor and ERK1/2 phosphorylation are inhibited by intraventricular administration of (a) AG 1478, a specific inhibitor of the receptor-tyrosine kinase of the EGF receptor; (b) GM 6001, an inhibitor of metalloproteinase(s) required for release of EGF receptor agonists from membrane-bound precursors; or (c) heparin, neutralizing heparin-binding EGF (HB-EGF). Thus, in intact brain HB-EGF, known to be expressed in brain, may be the major EGF agonist released in response to stimulation of α2-adrenoceptors, the released agonist(s) activate(s) EGF receptors, and ERK1/2 is phosphorylated as a conventional response to EGF receptor activation. Our previous paper (see above) showed that dexmedetomidine evokes no ERK1/2 phosphorylation in cultured neurons, but neurons respond to astrocyte-conditioned medium (and to EGF) with ERK1/2 phosphorylation. The present findings therefore suggest that EGF receptor transactivation in astrocytes in the mature brain in vivo is an important process in response to α2-adrenoceptor stimulation and may lead to phosphorylation of ERK1/2 both in astrocytes themselves and in adjacent neurons. [Copyright &y& Elsevier]

Fluoxetine has relatively high affinity for Gq/11 protein-coupled 5-HT2 receptors. Part of these receptors in brain are on astrocytes, where fluoxetine causes an increase in free cytosolic calcium concentration ([Ca2+]i) and phosphorylation of extracellular regulated kinase 1 and 2 (ERK1/2). The objectives of the study are to identify subtype of the 5-HT2 receptor involved, to establish whether ERK1/2 phosphorylation is a result of 5-HT2-mediated transactivation of epidermal growth factor (EGF) receptors (EGFRs), and to determine signaling pathways up- and downstream of ERK1/2. Primary cultures of mouse astrocytes, which express all three subtypes of the 5-HT2 receptor but no 5-HT2 transporter, were used. ERK1/2 phosphorylation and c-Fos and FosB protein expression were determined with Western blotting, and c-fos and fosB mRNA expression with reverse transcription polymerase chain reaction. Receptor subtype was investigated with subtype-specific 5-HT antagonists and 5-HT2B receptor depletion and signaling pathways by EGFR phosphorylation, using immunoprecipitation and Western blotting, inhibition of protein kinase C (PKC), and [Ca2+]i chelation by BAPTA/AM. ERK1/2 phosphorylation was abolished by SB204741, a universal 5-HT2 receptor antagonist, and in 5-HT2B receptor-depleted cells, but unaffected by 5-HT2A or 5-HT2C receptor antagonists (M100907 and SB242084). Phosphorylation of ERK1/2 and EGFRs was abolished by AG 1478, an inhibitor of EGFR tyrosine kinases, and GM 6001, an inhibitor of Zn-dependent metalloproteinases, suggesting growth factor “shedding” and transactivation of EGFRs. Chelation of [Ca2+]i or PKC inhibition with GF 109203X abrogated ERK1/2 phosphorylation. Up-regulated mRNA and protein expression of c-fos and fosB was abolished by SB204741, AG1478, and by U0126, an inhibitor of ERK phosphorylation by MAP kinase/ERK kinase. [ABSTRACT FROM AUTHOR]

Posttraumatic stress disorder (PTSD) is very common after exposure to trauma, mental stress or violence. Because objective biological markers for PTSD are lacking, exactly diagnosing PTSD is a challenge for clinical psychologists. In-depth research on the pathogenesis of PTSD is a key for solving this problem. In this work, we used male Thy1-YFP transgenic mice, in which neurons are fluorescently labeled, to research the effects of PTSD on neurons in vivo. We initially discovered that pathological stress associated with PTSD increased the activation of glycogen synthesis kinase-beta (GSK-3β) in neurons and induced the translocation of the transcription factor forkhead box-class O3a (FoxO3a) from the cytoplasm to the nucleus, which decreased the expression of uncoupling protein 2 (UCP2) and increased mitochondrial production of reactive oxygen species (ROS) to trigger neuronal apoptosis in the prefrontal cortex (PFC). Furthermore, the PTSD model mice showed increased freezing and anxiety-like behaviors and more severe decrease of memory and exploratory behavior. Additionally, leptin attenuated neuronal apoptosis by increasing the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which further elevated the expression of UCP2 and inhibited the mitochondrial production of ROS induced by PTSD, thus reducing neuronal apoptosis and ameliorating PTSD-related behaviors. Our study is expected to promote the exploration of PTSD-related pathogenesis in neural cells and the clinical effectiveness of leptin for PTSD. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that the activation of nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome contributes to the pathophysiology of post-traumatic stress disorder (PTSD). Astrocytes, the homeostatic cells of the central nervous system are intimately involved into pathophysiology of various mental disorders including PTSD. We demonstrated previously that leptin exerts neuroprotection and ameliorates chronic sleep deprivation-induced depressive-like behaviours. Here, we extended the study of therapeutic effects of leptin to PTSD model mice. We discovered that PTSD is associated with significant activation of NLRP3 inflammasome in astrocytes sorted from GFAP-GFP transgenic mice, while administration of leptin markedly suppressed the activation of astrocytic NLRP3 inflammasome. Leptin effectively improved PTSD-associated behavioural alterations including fear memory, cognitive impairments, and depressive-like behaviours. Therapeutic effects of leptin were mediated by the signal transducer and activator of transcription 3 (STAT3) in astrocytes. In addition, the PTSD-related activation of NLRP3 inflammasome impairs astrocytic mitochondria suppressing ATP synthesis and leading to an increased ROS production. Leptin reversed mitochondrial inhibition by stimulating STAT3 in astrocytes. We propose leptin as a novel candidate for the pharmacological treatment of PTSD. [ABSTRACT FROM AUTHOR]

Ketamine, as a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors, was originally used in general anesthesia. Epidemiological data show that ketamine has become one of the most commonly abused drugs in China. Ketamine administration might cause cognitive impairment; however, its molecular mechanism remains unclear. The glymphatic system is a lymphoid system that plays a key role in metabolic waste removal and cognitive regulation in the central nervous system. Focusing on the glymphatic system, this study evaluated the behavioral performance and circulatory function of the glymphatic system by building a short-term ketamine administration model in mice, and detected the expression levels of the 5-HT2c receptor, ΔFosb, Pten, Akt, and Aqp4 in the hippocampus. Primary astrocytes were cultured to verify the regulatory relationships among related indexes using a 5-HT2c receptor antagonist, a 5-HT2c receptor short interfering RNA (siRNA), and a ΔFosb siRNA. Ketamine administration induced ΔFosb accumulation by increasing 5-HT2c receptor expression in mouse hippocampal astrocytes and primary astrocytes. ΔFosb acted as a transcription factor to recognize the AATGATTAAT bases in the 5′ regulatory region of the Aqp4 gene (−1096 bp to −1087 bp), which inhibited Aqp4 expression, thus causing the circulatory dysfunction of the glymphatic system, leading to cognitive impairment. Although this regulatory mechanism does not involve the Pten/Akt pathway, this study revealed a new mechanism of ketamine-induced cognitive impairment in non-neuronal systems, and provided a theoretical basis for the safety of clinical treatment and the effectiveness of withdrawal. [Display omitted] • Ketamine administration causes circulatory dysfunction of glymphatic system. • Ketamine administration induces cognitive impairment in mice. • Ketamine induces ΔFosb accumulation by increasing the expression of 5-HT2c receptor. • ΔFosb acts as a transcription factor to recognize and inhibit Aqp4 expression. [ABSTRACT FROM AUTHOR]

Multiple sevoflurane exposures may damage the developing brain. The neuroprotective function of dexmedetomidine has been widely confirmed in animal experiments and human studies. However, the effect of dexmedetomidine on the glymphatic system has not been clearly studied. We hypothesized that dexmedetomidine could alleviate sevoflurane-induced circulatory dysfunction of the glymphatic system in young mice. Six-day-old C57BL/6 mice were exposed to 3% sevoflurane for 2 h daily, continuously for 3 days. Intraperitoneal injection of either normal saline or dexmedetomidine was administered before every anaesthesia. Meanwhile the circulatory function of glymphatic system was detected by tracer injection at P8 and P32. On P30-P32, behavior tests including open field test, novel object recognition test, and Y-maze test were conducted. Primary astrocyte cultures were established and treated with the PI3K activator 740Y-P, dexmedetomidine, and small interfering RNA (siRNA) to silence ΔFosB. We propose for the first time that multiple exposure to sevoflurane induces circulatory dysfunction of the glymphatic system in young mice. Dexmedetomidine improves the circulatory capacity of the glymphatic system in young mice following repeated exposure to sevoflurane through the PI3K/AKT/ΔFosB/AQP4 signaling pathway, and enhances their long-term learning and working memory abilities., (© 2024. The Author(s).)

Ketamine as a glutamate receptor antagonist has a rapid, potent, and long-lasting antidepressant effect, but its specific mechanism is still not fully understood. Depression is associated with elevated levels of glutamate and astrocyte loss in the brain; the exploration of the relationships between ketamine's antidepressant effect and astrocytes has drawn great attention. Astrocytes and aquaporin 4 (AQP4) are essential components of the glymphatic system, which is a brain-wide perivascular pathway to help transport nutrients to the parenchyma and remove metabolic wastes. In this study, we investigated pyroptosis-associated protein Nlrp3/Caspase-1/Gsdmd-N expression in the hippocampus of mice and the toxic effect of high levels of glutamate on primary astrocytes. On this basis, the protective mechanism of ketamine is explored. A single administration of ketamine (10 mg/kg) remarkably relieved anxious and depressive behaviors in the sucrose preference test, elevated plus maze test, and forced swim test. Meanwhile, ketamine reduced the level of hippocampus Nlrp3 and the expression of its downstream molecules in chronic unpredictable mild stress (CUMS) mice model by western blot and reduced the colocalization of Gfap and Gsdmd by nearly 25% via immunofluorescent staining. Ketamine also increased the Gfap-positive cells and AQP4 expression in the hippocampus of the CUMS mice. More important, ketamine increased the distribution of the fluorescent tracer of CUMS mice. Treatment with 128 mM glutamate in cortical and hippocampus astrocytes increased the level of Nlrp3, and Gsdmd-N, and ketamine alleviated high glutamate-induced pyroptosis-associated proteins. In summary, these results suggest that high glutamate-induced astrocyte pyroptosis through the Nlrp3/Caspase-1/Gsdmd-N pathway which was inhibited by ketamine and ketamine can improve the damaged glymphatic function of the CUMS mice. The present study indicates that inhibiting astrocyte pyroptosis and promoting the glymphatic circulation function are a new mechanism of ketamine's antidepressant effect, and astrocyte pyroptosis may be a new target for other antidepressant medicines., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Several trace metals, including iron, copper, manganese and zinc are essential for normal function of the nervous system. Both deficiency and excessive accumulation of these metals trigger neuropathological developments. The central nervous system (CNS) is in possession of dedicated homeostatic system that removes, accumulates, stores and releases these metals to fulfil nervous tissue demand. This system is mainly associated with astrocytes that act as dynamic reservoirs for trace metals, these being a part of a global system of CNS ionostasis. Here we overview physiological and pathophysiological aspects of astrocyte-cantered trace metals regulation., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Worldwide, the incidence of major depressive disorder (MDD) is increasing annually, resulting in greater economic and social burdens. Moreover, the pathological mechanisms of MDD and the mechanisms underlying the effects of pharmacological treatments for MDD are complex and unclear, and additional diagnostic and therapeutic strategies for MDD still are needed. The currently widely accepted theories of MDD pathogenesis include the neurotransmitter and receptor hypothesis, hypothalamic-pituitary-adrenal (HPA) axis hypothesis, cytokine hypothesis, neuroplasticity hypothesis and systemic influence hypothesis, but these hypothesis cannot completely explain the pathological mechanism of MDD. Even it is still hard to adopt only one hypothesis to completely reveal the pathogenesis of MDD, thus in recent years, great progress has been made in elucidating the roles of multiple organ interactions in the pathogenesis MDD and identifying novel therapeutic approaches and multitarget modulatory strategies, further revealing the disease features of MDD. Furthermore, some newly discovered potential pharmacological targets and newly studied antidepressants have attracted widespread attention, some reagents have even been approved for clinical treatment and some novel therapeutic methods such as phototherapy and acupuncture have been discovered to have effective improvement for the depressive symptoms. In this work, we comprehensively summarize the latest research on the pathogenesis and diagnosis of MDD, preventive approaches and therapeutic medicines, as well as the related clinical trials., (© 2024. The Author(s).)

Astroglia are a broad class of neural parenchymal cells primarily dedicated to homoeostasis and defence of the central nervous system (CNS). Astroglia contribute to the pathophysiology of all neurological and neuropsychiatric disorders in ways that can be either beneficial or detrimental to disorder outcome. Pathophysiological changes in astroglia can be primary or secondary and can result in gain or loss of functions. Astroglia respond to external, non-cell autonomous signals associated with any form of CNS pathology by undergoing complex and variable changes in their structure, molecular expression, and function. In addition, internally driven, cell autonomous changes of astroglial innate properties can lead to CNS pathologies. Astroglial pathophysiology is complex, with different pathophysiological cell states and cell phenotypes that are context-specific and vary with disorder, disorder-stage, comorbidities, age, and sex. Here, we classify astroglial pathophysiology into (i) reactive astrogliosis, (ii) astroglial atrophy with loss of function, (iii) astroglial degeneration and death, and (iv) astrocytopathies characterised by aberrant forms that drive disease. We review astroglial pathophysiology across the spectrum of human CNS diseases and disorders, including neurotrauma, stroke, neuroinfection, autoimmune attack and epilepsy, as well as neurodevelopmental, neurodegenerative, metabolic and neuropsychiatric disorders. Characterising cellular and molecular mechanisms of astroglial pathophysiology represents a new frontier to identify novel therapeutic strategies., (© 2023. West China Hospital, Sichuan University.)

Neuropathological mechanisms of manic syndrome or manic episodes in bipolar disorder remain poorly characterised, as the research progress is severely limited by the paucity of appropriate animal models. Here we developed a novel mania mice model by combining a series of chronic unpredictable rhythm disturbances (CURD), which include disruption of circadian rhythm, sleep deprivation, exposure to cone light, with subsequent interference of followed spotlight, stroboscopic illumination, high-temperature stress, noise disturbance and foot shock. Multiple behavioural and cell biology tests comparing the CURD-model with healthy controls and depressed mice were deployed to validate the model. The manic mice were also tested for the pharmacological effects of various medicinal agents used for treating mania. Finally, we compared plasma indicators of the CURD-model mice and the patients with the manic syndrome. The CURD protocol produced a phenotype replicating manic syndrome. Mice exposed to CURD presented manic behaviours similar to that observed in the amphetamine manic model. These behaviours were distinct from depressive-like behaviours recorded in mice treated with a depression-inducing protocol of chronic unpredictable mild restraint (CUMR). Functional and molecular indicators in the CURD mania model showed multiple similarities with patients with manic syndrome. Treatment with LiCl and valproic acid resulted in behavioural improvements and recovery of molecular indicators. A novel manic mice model induced by environmental stressors and free from genetic or pharmacological interventions is a valuable tool for research into pathological mechanisms of mania., (© 2023. The Author(s).)

Although posttraumatic stress disorder (PTSD) is on the rise, traumatic events and their consequences are often hidden or minimized by patients for reasons linked to PTSD itself. Traumatic experiences can be broadly classified into mental stress (MS) and traumatic brain injury (TBI), but the cellular mechanisms of MS- or TBI-induced PTSD remain unknown. Recent evidence has shown that the morphological remodeling of astrocytes accompanies and arguably contributes to fearful memories and stress-related disorders. In this review, we summarize the roles of astrocytes in the pathogenesis of MS-PTSD and TBI-PTSD. Astrocytes synthesize and secrete neurotrophic, pro- and anti-inflammatory factors and regulate the microenvironment of the nervous tissue through metabolic pathways, ionostatic control, and homeostatic clearance of neurotransmitters. Stress or trauma-associated impairment of these vital astrocytic functions contribute to the pathophysiological evolution of PTSD and may present therapeutic targets., (© 2022. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences.)

Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, exerts rapid, potent and long-lasting antidepressant effect already after a single administration of a low dose into depressed individuals. Apart from targeting neuronal NMDARs essential for synaptic transmission, ketamine also interacts with astrocytes, the principal homoeostatic cells of the central nervous system. The cellular mechanisms underlying astrocyte-based rapid antidepressant effect are incompletely understood. Here we overview recent data that describe ketamine-dependent changes in astrocyte cytosolic cAMP activity ([cAMP] i ) and ketamine-induced modifications of stimulus-evoked Ca 2+ signalling. The latter regulates exocytotic release of gliosignalling molecules and stabilizes the vesicle fusion pore in a narrow configuration that obstructs cargo discharge or vesicle membrane recycling. Ketamine also instigates rapid redistribution of cholesterol in the astrocyte plasmalemma that may alter flux of cholesterol to neurones, where it is required for changes in synaptic plasticity. Finally, ketamine attenuates mobility of vesicles carrying the inward rectifying potassium channel (K ir 4.1) and reduces the surface density of K ir 4.1 channels that control extracellular K + concentration, which tunes the pattern of action potential firing in neurones of lateral habenula as demonstrated in a rat model of depression. Thus, diverse, but not mutually exclusive, mechanisms act synergistically to evoke changes in synaptic plasticity leading to sustained strengthening of excitatory synapses necessary for rapid antidepressant effect of ketamine., (© 2021. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Astroglia are a diverse group of cells in the central nervous system. They are of the ectodermal, neuroepithelial origin and vary in morphology and function, yet, they can be collectively defined as cells having principle function to maintain homeostasis of the central nervous system at all levels of organisation, including homeostasis of ions, pH and neurotransmitters; supplying neurones with metabolic substrates; supporting oligodendrocytes and axons; regulating synaptogenesis, neurogenesis, and formation and maintenance of the blood-brain barrier; contributing to operation of the glymphatic system; and regulation of systemic homeostasis being central chemosensors for oxygen, CO 2 and Na + . Their basic physiological features show a lack of electrical excitability (inapt to produce action potentials), but display instead a rather active excitability based on variations in cytosolic concentrations of Ca 2+ and Na + . It is expression of neurotransmitter receptors, pumps and transporters at their plasmalemma, along with transports on the endoplasmic reticulum and mitochondria that exquisitely regulate the cytosolic levels of these ions, the fluctuation of which underlies most, if not all, astroglial homeostatic functions., (© 2021. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

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., (© 2021. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

The role of astrocytes in the nervous system pathology was early on embraced by neuroscientists at end of the nineteenth and the beginning of the twentieth century, only to be pushed aside by neurone-centric dogmas during most of the twentieth century. However, the last decade of the twentieth century and the twenty-first century have brought the astroglial "renaissance", which has put astroglial cells as key players in pathophysiology of most if not all disorders of the nervous system and has regarded astroglia as a fertile ground for therapeutic intervention.Astrocytic contribution to neuropathology can be primary, whereby cell-autonomous changes, such as mutations in gene encoding for glial fibrillary acidic protein, can drive the pathologic progression, in this example, Alexander disease. They can also be secondary, when astrocytes respond to a variety of insults to the nervous tissue. Regardless of their origin, being cell-autonomous or not, changes in astroglia that occur in pathology, that is, astrogliopathology, can be contemporary and arbitrary classified into four forms: (i) reactive astrogliosis, (ii) astrocytic atrophy with loss of function, (iii) pathological remodelling of astrocytes and (iv) astrodegeneration morphologically manifested as clasmatodendrosis. Inevitably, as with any other classification, this classification of astrogliopathology awaits its revision that shall be rooted in new discoveries and concepts., (© 2021. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

The long-lasting loss of sleep is a generally acknowledged risk factor for the occurrence of major depressive disorder (MDD), whereas sleep abnormalities being a key clinic symptom of the MDD. In our previous work, we demonstrated that the sleep deprivation (SD) stimulates activation of nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasomes as well as the release of IL-1β and IL-18 from astrocytes. However, the underlying mechanism connecting SD and MDD still requires further study. Apart of the secretion of the pro-inflammatory cytokines, SD affects production of brain-derived neurotrophic factor (BDNF) while release of BDNF from astrocytes appears a key contributor to mood disorders. If and how the activation of NLRP3 inflammasome following SD affects the level of BDNF remains unknown. Antidepressant fluoxetine acts through astroglial 5-hydroxytryptamine receptor 2B (5-HT 2B ); these receptors are also related to the sleep-wake cycle. Contribution of leptin to MDD has been discovered recently, although the mechanistic links between leptin and the depressive-like behaviors has not been revealed. In this study, we discovered: (i) that activation of NLRP3 inflammasome was involved in the depressive-like behaviors induced by SD; (ii) decrease in BDNF following SD required the activation of NLRP3 inflammasomes; (iii) leptin augmented the anti-depressive action of fluoxetine through an increase in expression of astrocytic 5-HT 2B receptors. We suggest that decrease in BDNF by the activated NLRP3 inflammasomes in astrocytes is the key pathological event of the depressive-like behaviors induced by SD, while the combined treatment with fluoxetine and leptin improves therapeutic outcome for the depression induced by SD.

Introduction : Astroglia represent the main cellular homeostatic system of the central nervous system (CNS). Astrocytes are intimately involved in regulation and maintenance of neurotransmission by regulating neurotransmitters removal and turnover and by supplying neurons with neurotransmitters precursors. Astroglial cells are fundamental elements of monoaminergic transmission in the brain and in the spinal cord. Astrocytes receive monoaminergic inputs and control catabolism of monoamines through dedicated transporters and intracellular enzymatic pathways. Areas covered : Astroglial cells express serotonergic receptors; in this review, we provide an in-depth characterization of 5-HT 2B receptors. Activation of these receptors triggers numerous intracellular signaling cascades that regulate expression of multiple genes. Astroglial 5-HT 2B receptors are activated by serotonin-specific reuptake inhibitors, such as major anti-depressant fluoxetine. Expression of astroglial serotonin receptors undergoes remarkable changes in depression disorders, and these changes can be corrected by chronic treatment with anti-depressant drugs. Expert commentary : Depressive behaviors, which occur in rodents following chronic stress or in neurotoxic models of Parkinson disease, are associated with significant changes in the expression of astroglial, but not neuronal 5-HT 2B receptors; while therapy with anti-depressants normalizes both receptors expression and depressive behavioral phenotype. In summary, astroglial serotonin receptors are linked to mood disorders and may represent a novel target for cell- and molecule-specific therapies of depression and mood disorders.

It is well known that sleep disorders are harmful to people's health and performance, and growing evidence suggests that sleep deprivation (SD) can trigger neuroinflammation in the brain. The nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome is reported to be relevant to the neuroinflammation induced by SD, but the regulatory signaling that governs the NLRP3 inflammasome in SD is still unknown. Meanwhile, whether the regulatory action of antidepressants in astrocytes could affect the neuroinflammation induced by SD also remains obscure. In this study, we were the first to discover that the antidepressant fluoxetine, a type of specific serotonin reuptake inhibitor widely used in clinical practice, could suppress the neuroinflammation and neuronal apoptosis induced by SD. The main findings from this study are as follows: (i) SD stimulated the expression of activated NLRP3 inflammasomes and the maturation of IL-1β/18 via suppressing the phosphorylation of STAT3 in astrocytes; (ii) SD decreased the activation of AKT and stimulated the phosphorylation of GSK-3β, which inhibited the phosphorylation of STAT3; (iii) the NLRP3 inflammasome expression stimulated by SD was partly mediated by the P2X7 receptor; (iv) an agonist of STAT3 could significantly abolish the expression of NLRP3 inflammasomes induced by an agonist of the P2X7 receptor in primary cultured astrocytes; (v) the administration of fluoxetine could reverse the stimulation of NLRP3 inflammasome expression and function by SD through elevating the activation of STAT3. In conclusion, our present research suggests the promising possibility that fluoxetine could ameliorate the neuronal impairment induced by SD., (© 2017 International Society for Neurochemistry.)