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

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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 15235

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Dr. Guillaume Lucas

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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

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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

Published Papers (6 papers)

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Research

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19 pages, 2888 KiB

Open AccessArticle

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

Viewed by 771

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 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

Open AccessArticle

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 1508

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 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

Open AccessArticle

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 8 | Viewed by 1877

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 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

Open AccessReview

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 1 | Viewed by 1653

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. 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

Open AccessReview

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 7 | Viewed by 6414

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 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

Open AccessBrief 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 4 | Viewed by 1489

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 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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