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Roles of Glia in CNS: Toward the Development of New Antidepressant Strategies?

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 19836

Special Issue Editor

Dr. Guillaume Lucas

E-Mail Website
Guest Editor
Head, Team P3TN, INCIA CNRS UMR 5287, 146 rue Léo-Saignat, 33076 Bordeaux, France
Interests: antidepressants; serotonin system; neuroplasticity; hippocampus; brain stimulation; spinogenesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The amount of data indicating that glial cells do not only act as structural or logistical support within the CNS but actively participate in the processes of neurotransmission and neural plasticity is growing exponentially. It is now widely accepted that astrocytes, microglial cells, and oligodendrocytes are involved in virtually all brain activities, ranging from the regulation of central homeostasis to memory or the elaboration of superior functions. Among their multiple aspects, the role played by glial cells in the control of mood and emotion appears to be particularly illustrative of such an ability to closely co-operate with neurons. Numerous studies have already highlighted the importance of neuro-inflammation in the emergence of depression or depression-like behaviors, and, not surprisingly, the effect of microglial cells was found to be major. Specifically targeting the molecular actors involved in this process has recently been proposed as a potential antidepressant strategy. Furthermore, a growing amount of evidence suggests that astrocytes may also contribute to antidepressant mechanisms. Thus, it appears that one requirement for antidepressant efficiency is an increase in synaptic plasticity within some limbic and associative brain areas, such as the prefrontal cortex or the hippocampus. Taking into account the fundamental importance of astrocytes in the tripartite synapse, it is therefore likely that strategies aimed at reinforcing their molecular impact on plasticity mechanisms may be of relevance in the search for new classes of antidepressants. Finally, besides their well-known role in the genesis and maintenance of myelin, oligodendrocytes have more recently been shown to be enrolled in some neuro-inflammatory conditions, which might be of interest in the context of antidepressant research.

This Special Issue will welcome both research papers and reviews addressing these points, with a particular interest in those focusing on molecular mechanisms.

Dr. Guillaume Lucas
Guest Editor

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Keywords

  • glial cells
  • astrocytes
  • microglia
  • neuro-inflammation
  • synaptic plasticity
  • antidepressant strategies

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Published Papers (7 papers)

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Research

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19 pages, 3078 KiB  
Article
GSP1-111 Modulates the Microglial M1/M2 Phenotype by Inhibition of Toll-like Receptor 2: A Potential Therapeutic Strategy for Depression
by Ryeong-Eun Kim, Darine Froy Mabunga, Kyung-Jun Boo, Dong Hyun Kim, Seol-Heui Han, Chan Young Shin and Kyoung Ja Kwon
Int. J. Mol. Sci. 2024, 25(19), 10594; https://doi.org/10.3390/ijms251910594 - 1 Oct 2024
Viewed by 613
Abstract
Neuroinflammation plays a vital role in neurodegenerative diseases and neuropsychiatric disorders, and microglia and astrocytes chiefly modulate inflammatory responses in the central nervous system (CNS). Toll-like receptors (TLRs), which are expressed in neurons, astrocytes, and microglia in the CNS, are critical for innate [...] Read more.
Neuroinflammation plays a vital role in neurodegenerative diseases and neuropsychiatric disorders, and microglia and astrocytes chiefly modulate inflammatory responses in the central nervous system (CNS). Toll-like receptors (TLRs), which are expressed in neurons, astrocytes, and microglia in the CNS, are critical for innate immune responses; microglial TLRs can regulate the activity of these cells, inducing protective or harmful effects on the surrounding cells, including neurons. Therefore, regulating TLRs in microglia may be a potential therapeutic strategy for neurological disorders. We examined the protective effects of GSP1-111, a novel synthetic peptide for inhibiting TLR signaling, on neuroinflammation and depression-like behavior. GSP1-111 decreased TLR2 expression and remarkably reduced the mRNA expression of inflammatory M1-phenotype markers, including tumor necrosis factor (TNF)α, interleukin (IL)-1β, and IL-6, while elevating that of the M2 phenotype markers, Arg-1 and IL-10. In vivo, GSP1-111 administration significantly decreased the depression-like behavior induced by lipopolysaccharide (LPS) in a forced swim test and significantly reduced the brain levels of M1-specific inflammatory cytokines (TNFα, IL-1β, and IL-6). GSP1-111 prevented the LPS-induced microglial activation and TLR2 expression in the brain. Accordingly, GSP1-111 prevented inflammatory responses and induced microglial switching of the inflammatory M1 phenotype to the protective M2 phenotype. Thus, GSP1-111 could prevent depression-like behavior by inhibiting TLR2. Taken together, our results suggest that the TLR2 pathway is a promising therapeutic target for depression, and GSP1-111 could be a novel therapeutic candidate for various neurological disorders. Full article
(This article belongs to the Special Issue Roles of Glia in CNS: Toward the Development of New Antidepressant Strategies?)
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19 pages, 2888 KiB  
Article
Anti-Neuroinflammatory Effects of a Macrocyclic Peptide-Peptoid Hybrid in Lipopolysaccharide-Stimulated BV2 Microglial Cells
by Lu Sun, Soraya Wilke Saliba, Matthias Apweiler, Kamil Akmermer, Claudine Herlan, Christoph Grathwol, Antônio Carlos Pinheiro de Oliveira, Claus Normann, Nicole Jung, Stefan Bräse and Bernd L. Fiebich
Int. J. Mol. Sci. 2024, 25(8), 4462; https://doi.org/10.3390/ijms25084462 - 18 Apr 2024
Cited by 1 | Viewed by 1590
Abstract
Inflammation processes of the central nervous system (CNS) play a vital role in the pathogenesis of several neurological and psychiatric disorders like depression. These processes are characterized by the activation of glia cells, such as microglia. Clinical studies showed a decrease in symptoms [...] Read more.
Inflammation processes of the central nervous system (CNS) play a vital role in the pathogenesis of several neurological and psychiatric disorders like depression. These processes are characterized by the activation of glia cells, such as microglia. Clinical studies showed a decrease in symptoms associated with the mentioned diseases after the treatment with anti-inflammatory drugs. Therefore, the investigation of novel anti-inflammatory drugs could hold substantial potential in the treatment of disorders with a neuroinflammatory background. In this in vitro study, we report the anti-inflammatory effects of a novel hexacyclic peptide-peptoid hybrid in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. The macrocyclic compound X15856 significantly suppressed Interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), c-c motif chemokine ligand 2 (CCL2), CCL3, C-X-C motif chemokine ligand 2 (CXCL2), and CXCL10 expression and release in LPS-treated BV2 microglial cells. The anti-inflammatory effects of the compound are partially explained by the modulation of the phosphorylation of p38 mitogen-activated protein kinases (MAPK), p42/44 MAPK (ERK 1/2), protein kinase C (PKC), and the nuclear factor (NF)-κB, respectively. Due to its remarkable anti-inflammatory properties, this compound emerges as an encouraging option for additional research and potential utilization in disorders influenced by inflammation, such as depression. Full article
(This article belongs to the Special Issue Roles of Glia in CNS: Toward the Development of New Antidepressant Strategies?)
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16 pages, 4442 KiB  
Article
Prolonged Febrile Seizures Impair Synaptic Plasticity and Alter Developmental Pattern of Glial Fibrillary Acidic Protein (GFAP)-Immunoreactive Astrocytes in the Hippocampus of Young Rats
by Alexandra V. Griflyuk, Tatyana Y. Postnikova and Aleksey V. Zaitsev
Int. J. Mol. Sci. 2022, 23(20), 12224; https://doi.org/10.3390/ijms232012224 - 13 Oct 2022
Cited by 5 | Viewed by 1871
Abstract
Prolonged neonatal febrile seizures (FSs) often lead to cognitive decline and increased risk of psychopathology in adulthood. However, the neurobiological mechanisms underlying the long-term adverse effects of FSs remain unclear. In this study, we exposed rat pups to hyperthermia and induced FSs lasting [...] Read more.
Prolonged neonatal febrile seizures (FSs) often lead to cognitive decline and increased risk of psychopathology in adulthood. However, the neurobiological mechanisms underlying the long-term adverse effects of FSs remain unclear. In this study, we exposed rat pups to hyperthermia and induced FSs lasting at least 15 min. We investigated the short-term (one day) and delayed (11–13 and 41–45 days) effects of FSs on some parameters of morphological and functional maturation in the hippocampus. We noticed that FSs altered the developmental pattern of glial fibrillary acidic protein (GFAP) immunoreactivity. In rats aged 21–23 days, GFAP-positive astrocytes covered a smaller area, and their morphological characteristics resembled those of rats at 11 days of age. In post-FS rats, the magnitude of long-term synaptic potentiation was reduced compared to control animals of the same age. Applying the gliotransmitter D-serine, an agonist of the glycine site of NMDA receptors, restored LTP to control values. A decrease in LTP amplitude was correlated with impaired spatial learning and memory in the Barnes maze task in post-FS rats. Our data suggest that impaired neuron–glia interactions may be an essential mechanism of the adverse effects of FS on the developing brain. Full article
(This article belongs to the Special Issue Roles of Glia in CNS: Toward the Development of New Antidepressant Strategies?)
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19 pages, 3313 KiB  
Article
Dose-Dependent Biphasic Action of Quetiapine on AMPK Signalling via 5-HT7 Receptor: Exploring Pathophysiology of Clinical and Adverse Effects of Quetiapine
by Motohiro Okada, Kouji Fukuyama and Eishi Motomura
Int. J. Mol. Sci. 2022, 23(16), 9103; https://doi.org/10.3390/ijms23169103 - 14 Aug 2022
Cited by 9 | Viewed by 2290
Abstract
Recent pharmacological studies indicated that the modulation of tripartite-synaptic transmission plays important roles in the pathophysiology of schizophrenia, mood disorders and adverse reactions. Therefore, to explore the mechanisms underlying the clinical and adverse reactions to atypical antipsychotics, the present study determined the effects [...] Read more.
Recent pharmacological studies indicated that the modulation of tripartite-synaptic transmission plays important roles in the pathophysiology of schizophrenia, mood disorders and adverse reactions. Therefore, to explore the mechanisms underlying the clinical and adverse reactions to atypical antipsychotics, the present study determined the effects of the sub-chronic administration of quetiapine (QTP: 3~30 μM) on the protein expression of 5-HT7 receptor (5-HT7R), connexin43 (Cx43), cAMP level and intracellular signalling, Akt, Erk and adenosine monophosphate-activated protein kinase (AMPK) in cultured astrocytes and the rat hypothalamus, using ultra-high-pressure liquid chromatography with mass spectrometry and capillary immunoblotting systems. QTP biphasically increased physiological ripple-burst evoked astroglial D-serine release in a concentration-dependent manner, peaking at 10 μM. QTP enhanced the astroglial signalling of Erk concentration-dependently, whereas both Akt and AMPK signalling’s were biphasically enhanced by QTP, peaking at 10 μM and 3 μM, respectively. QTP downregulated astroglial 5-HT7R in the plasma membrane concentration-dependently. Protein expression of Cx43 in astroglial cytosol and intracellular cAMP levels were decreased and increased by QTP also biphasically, peaking at 3 μM. The dose-dependent effects of QTP on the protein expression of 5-HT7R and Cx43, AMPK signalling and intracellular cAMP levels in the hypothalamus were similar to those in astrocytes. These results suggest several complicated pharmacological features of QTP. A therapeutically relevant concentration/dose of QTP activates Akt, Erk and AMPK signalling, whereas a higher concentration/dose of QTP suppresses AMPK signalling via its low-affinity 5-HT7R inverse agonistic action. Therefore, 5-HT7R inverse agonistic action probably plays important roles in the prevention of a part of adverse reactions of QTP, such as weight gain and metabolic complications. Full article
(This article belongs to the Special Issue Roles of Glia in CNS: Toward the Development of New Antidepressant Strategies?)
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Review

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16 pages, 626 KiB  
Review
Potential Inflammatory Biomarkers for Major Depressive Disorder Related to Suicidal Behaviors: A Systematic Review
by Ka Young Kim, Ki Young Shin and Keun-A Chang
Int. J. Mol. Sci. 2023, 24(18), 13907; https://doi.org/10.3390/ijms241813907 - 9 Sep 2023
Cited by 4 | Viewed by 2744
Abstract
Major depressive disorder (MDD) is a highly prevalent psychiatric condition affecting an estimated 280 million individuals globally. Despite the occurrence of suicidal behaviors across various psychiatric conditions, MDD is distinctly associated with the highest risk of suicide attempts and death within this population. [...] Read more.
Major depressive disorder (MDD) is a highly prevalent psychiatric condition affecting an estimated 280 million individuals globally. Despite the occurrence of suicidal behaviors across various psychiatric conditions, MDD is distinctly associated with the highest risk of suicide attempts and death within this population. In this study, we focused on MDD to identify potential inflammatory biomarkers associated with suicidal risk, given the relationship between depressive states and suicidal ideation. Articles published before June 2023 were searched in PubMed, Embase, Web of Science, and the Cochrane Library to identify all relevant studies reporting blood inflammatory biomarkers in patients with MDD with suicide-related behaviors. Of 571 articles, 24 were included in this study. Overall, 43 significant biomarkers associated with MDD and suicide-related behaviors were identified. Our study provided compelling evidence of significant alterations in peripheral inflammatory factors in MDD patients with suicide-related behaviors, demonstrating the potential roles of interleukin (IL)-1β, IL-6, C-reactive protein, C-C motif chemokine ligand 2, and tumor necrosis factor-α as biomarkers. These findings underscore the intricate relationship between the inflammatory processes of these biomarkers and their interactions in MDD with suicidal risk. Full article
(This article belongs to the Special Issue Roles of Glia in CNS: Toward the Development of New Antidepressant Strategies?)
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27 pages, 1564 KiB  
Review
Depression Pathophysiology: Astrocyte Mitochondrial Melatonergic Pathway as Crucial Hub
by George Anderson
Int. J. Mol. Sci. 2023, 24(1), 350; https://doi.org/10.3390/ijms24010350 - 26 Dec 2022
Cited by 10 | Viewed by 7306
Abstract
Major depressive disorder (MDD) is widely accepted as having a heterogenous pathophysiology involving a complex mixture of systemic and CNS processes. A developmental etiology coupled to genetic and epigenetic risk factors as well as lifestyle and social process influences add further to the [...] Read more.
Major depressive disorder (MDD) is widely accepted as having a heterogenous pathophysiology involving a complex mixture of systemic and CNS processes. A developmental etiology coupled to genetic and epigenetic risk factors as well as lifestyle and social process influences add further to the complexity. Consequently, antidepressant treatment is generally regarded as open to improvement, undoubtedly as a consequence of inappropriately targeted pathophysiological processes. This article reviews the diverse array of pathophysiological processes linked to MDD, and integrates these within a perspective that emphasizes alterations in mitochondrial function, both centrally and systemically. It is proposed that the long-standing association of MDD with suppressed serotonin availability is reflective of the role of serotonin as a precursor for the mitochondrial melatonergic pathway. Astrocytes, and the astrocyte mitochondrial melatonergic pathway, are highlighted as crucial hubs in the integration of the wide array of biological underpinnings of MDD, including gut dysbiosis and permeability, as well as developmental and social stressors, which can act to suppress the capacity of mitochondria to upregulate the melatonergic pathway, with consequences for oxidant-induced changes in patterned microRNAs and subsequent patterned gene responses. This is placed within a development context, including how social processes, such as discrimination, can physiologically regulate a susceptibility to MDD. Future research directions and treatment implications are derived from this. Full article
(This article belongs to the Special Issue Roles of Glia in CNS: Toward the Development of New Antidepressant Strategies?)
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Other

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13 pages, 2158 KiB  
Brief Report
Astroglial Connexins Inactivation Increases Relapse of Depressive-like Phenotype after Antidepressant Withdrawal
by Benjamin Portal, Flora Vasile, Jonathan Zapata, Camille Lejards, Abd El Kader Ait Tayeb, Romain Colle, Céline Verstuyft, Emmanuelle Corruble, Nathalie Rouach and Bruno P. Guiard
Int. J. Mol. Sci. 2022, 23(21), 13227; https://doi.org/10.3390/ijms232113227 - 30 Oct 2022
Cited by 5 | Viewed by 1796
Abstract
Studies suggest that astrocytic connexins (Cx) have an important role in the regulation of high brain functions through their ability to establish fine-tuned communication with neurons within the tripartite synapse. In light of these properties, growing evidence suggests a role of Cx in [...] Read more.
Studies suggest that astrocytic connexins (Cx) have an important role in the regulation of high brain functions through their ability to establish fine-tuned communication with neurons within the tripartite synapse. In light of these properties, growing evidence suggests a role of Cx in psychiatric disorders such as major depression but also in the therapeutic activity of antidepressant drugs. However, the real impact of Cx on treatment response and the underlying neurobiological mechanisms remain yet to be clarified. On this ground, the present study was designed to evaluate the functional activity of Cx in a mouse model of depression based on chronic corticosterone exposure and to determine to which extent their pharmacological inactivation influences the antidepressant-like activity of venlafaxine (VENLA). On the one hand, our results indicate that depressed mice have impaired Cx-based gap-junction and hemichannel activities. On the other hand, while VENLA exerts robust antidepressant-like activity in depressed mice; this effect is abolished by the pharmacological inhibition of Cx with carbenoxolone (CBX). Interestingly, the combination of VENLA and CBX is also associated with a higher rate of relapse after treatment withdrawal. To our knowledge, this study is one of the first to develop a model of relapse, and our results reveal that Cx-mediated dynamic neuroglial interactions play a critical role in the efficacy of monoaminergic antidepressant drugs, thus providing new targets for the treatment of depression. Full article
(This article belongs to the Special Issue Roles of Glia in CNS: Toward the Development of New Antidepressant Strategies?)
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