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Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention

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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 October 2020) | Viewed by 50503

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Dr. Agata Adamczyk

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Department of Cellular Signalling, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland
Interests: neurodegeneration; neuroinflammation; mitochondria failure; autism spectrum disorders; synaptic plasticity; signal transduction; oxidative/nitrosative stress; alpha-synuclein
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Special Issue Information

Dear Colleagues,

The central nervous system (CNS) function depends on both neurons and glial cells, and the interactions between these cells play critical roles in the functionality of the healthy CNS. However, genetic, molecular, and epidemiologic studies have also revealed the prominent and often causative roles of glial–neuronal interactions in the development or progression of many common neurodegenerative and neurodevelopmental disorders, including: Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, ischemia (stroke), multiple sclerosis, epilepsy, schizophrenia, as well as autism-spectrum disorders. Accumulation of misfolded proteins, impairment in protein trafficking and energy metabolism, oxidative stress, and formation of free radicals are common features for these pathological conditions. All these pathways are strongly regulated by glial cells in the CNS that are responsible for maintaining homeostasis on the cellular, metabolic, structural, and signaling transmission level. Therefore, the main goal of this Special Issue is to reveal directions and consequences of glial–neuronal interactions for improving our understanding of the pathomechanisms as well as for the development of potential new therapies for neurological disorders. Original manuscripts and reviews dealing with the implication of glial–neuronal interactions in the development or progression of neurodegenerative and neurodevelopmental disorders are very welcome from outstanding experts on the topic.

Dr. Agata Adamczyk
Guest Editor

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Keywords

Central nervous system
Glial–Neuronal interactions
Autism spectrum disorders
Neurodegenerative disorders
Neurodevelopmental disorders
Neuroinflammation
Synapses
Signal transduction

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Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention 2.0 in International Journal of Molecular Sciences (17 articles)

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Research

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20 pages, 9895 KiB

Open AccessArticle

Acute Systemic Inflammatory Response Alters Transcription Profile of Genes Related to Immune Response and Ca²⁺ Homeostasis in Hippocampus; Relevance to Neurodegenerative Disorders

by Grzegorz A. Czapski, Yuhai Zhao, Walter J. Lukiw and Joanna B. Strosznajder

Int. J. Mol. Sci. 2020, 21(21), 7838; https://doi.org/10.3390/ijms21217838 - 22 Oct 2020

Cited by 14 | Viewed by 3436

Abstract

Acute systemic inflammatory response (SIR) triggers an alteration in the transcription of brain genes related to neuroinflammation, oxidative stress and cells death. These changes are also characteristic for Alzheimer’s disease (AD) neuropathology. Our aim was to evaluate gene expression patterns in the mouse hippocampus (MH) by using microarray technology 12 and 96 h after SIR evoked by lipopolysaccharide (LPS). The results were compared with microarray analysis of human postmortem hippocampal AD tissues. It was found that 12 h after LPS administration the expression of 231 genes in MH was significantly altered (FC > 2.0); however, after 96 h only the S100a8 gene encoding calgranulin A was activated (FC = 2.9). Gene ontology enrichment analysis demonstrated the alteration of gene expression related mostly to the immune-response including the gene Lcn2 for Lipocalin 2 (FC = 237.8), involved in glia neurotoxicity. The expression of genes coding proteins involved in epigenetic regulation, histone deacetylases (Hdac4,5,8,9,11) and bromo- and extraterminal domain protein Brd3 were downregulated; however, Brd2 was found to be upregulated. Remarkably, the significant increase in expression of Lcn2, S100a8, S100a9 and also Saa3 and Ch25h, was found in AD brains suggesting that early changes of immune-response genes evoked by mild SIR could be crucial in AD pathogenesis. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention)

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17 pages, 6300 KiB

Open AccessArticle

Neuroimmune Response in Natural Preclinical Scrapie after Dexamethasone Treatment

by Isabel M. Guijarro, Moisés Garcés, Belén Marín, Alicia Otero, Tomás Barrio, Juan J. Badiola and Marta Monzón

Int. J. Mol. Sci. 2020, 21(16), 5779; https://doi.org/10.3390/ijms21165779 - 12 Aug 2020

Cited by 5 | Viewed by 2544

Abstract

A recently published report on chronic dexamethasone treatment for natural scrapie supported the hypothesis of the potential failure of astroglia in the advanced stage of disease. Herein, we aimed to extend the aforementioned study on the effect of this anti-inflammatory therapy to the initial phase of scrapie, with the aim of elucidating the natural neuroinflammatory process occurring in this neurodegenerative disorder. The administration of this glucocorticoid resulted in an outstanding reduction in vacuolation and aberrant protein deposition (nearly null), and an increase in glial activation. Furthermore, evident suppression of IL-1R and IL-6 and the exacerbation of IL-1α, IL-2R, IL-10R and IFNγR were also demonstrated. Consequently, the early stage of the disease is characterized by an intact neuroglial response similar to that of healthy individuals attempting to re-establish homeostasis. A complex network of neuroinflammatory markers is involved from the very early stages of this prion disease, which probably becomes impaired in the more advanced stages. The in vivo animal model used herein provides essential observations on the pathogenesis of natural scrapie, as well as the possibility of establishing neuroglia as potential target cells for anti-inflammatory therapy. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention)

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29 pages, 8514 KiB

Open AccessArticle

Maternal Immune Activation Induces Neuroinflammation and Cortical Synaptic Deficits in the Adolescent Rat Offspring

by Magdalena Cieślik, Magdalena Gąssowska-Dobrowolska, Henryk Jęśko, Grzegorz A. Czapski, Anna Wilkaniec, Aleksandra Zawadzka, Agnieszka Dominiak, Rafał Polowy, Robert K. Filipkowski, Paweł M. Boguszewski, Magdalena Gewartowska, Małgorzata Frontczak-Baniewicz, Grace Y. Sun, David Q. Beversdorf and Agata Adamczyk

Int. J. Mol. Sci. 2020, 21(11), 4097; https://doi.org/10.3390/ijms21114097 - 8 Jun 2020

Cited by 43 | Viewed by 6363

Abstract

Maternal immune activation (MIA), induced by infection during pregnancy, is an important risk factor for neuro-developmental disorders, such as autism. Abnormal maternal cytokine signaling may affect fetal brain development and contribute to neurobiological and behavioral changes in the offspring. Here, we examined the effect of lipopolysaccharide-induced MIA on neuro-inflammatory changes, as well as synaptic morphology and key synaptic protein level in cerebral cortex of adolescent male rat offspring. Adolescent MIA offspring showed elevated blood cytokine levels, microglial activation, increased pro-inflammatory cytokines expression and increased oxidative stress in the cerebral cortex. Moreover, pathological changes in synaptic ultrastructure of MIA offspring was detected, along with presynaptic protein deficits and down-regulation of postsynaptic scaffolding proteins. Consequently, ability to unveil MIA-induced long-term alterations in synapses structure and protein level may have consequences on postnatal behavioral changes, associated with, and predisposed to, the development of neuropsychiatric disorders. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention)

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33 pages, 7463 KiB

Open AccessArticle

Prenatal Exposure to Valproic Acid Affects Microglia and Synaptic Ultrastructure in a Brain-Region-Specific Manner in Young-Adult Male Rats: Relevance to Autism Spectrum Disorders

by Magdalena Gąssowska-Dobrowolska, Magdalena Cieślik, Grzegorz Arkadiusz Czapski, Henryk Jęśko, Małgorzata Frontczak-Baniewicz, Magdalena Gewartowska, Agnieszka Dominiak, Rafał Polowy, Robert Kuba Filipkowski, Lidia Babiec and Agata Adamczyk

Int. J. Mol. Sci. 2020, 21(10), 3576; https://doi.org/10.3390/ijms21103576 - 18 May 2020

Cited by 41 | Viewed by 6240

Abstract

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental conditions categorized as synaptopathies. Environmental risk factors contribute to ASD aetiology. In particular, prenatal exposure to the anti-epileptic drug valproic acid (VPA) may increase the risk of autism. In the present study, we investigated the effect of prenatal exposure to VPA on the synaptic morphology and expression of key synaptic proteins in the hippocampus and cerebral cortex of young-adult male offspring. To characterize the VPA-induced autism model, behavioural outcomes, microglia-related neuroinflammation, and oxidative stress were analysed. Our data showed that prenatal exposure to VPA impaired communication in neonatal rats, reduced their exploratory activity, and led to anxiety-like and repetitive behaviours in the young-adult animals. VPA-induced pathological alterations in the ultrastructures of synapses accompanied by deregulation of key pre- and postsynaptic structural and functional proteins. Moreover, VPA exposure altered the redox status and expression of proinflammatory genes in a brain region-specific manner. The disruption of synaptic structure and plasticity may be the primary insult responsible for autism-related behaviour in the offspring. The vulnerability of specific synaptic proteins to the epigenetic effects of VPA may highlight the potential mechanisms by which prenatal VPA exposure generates behavioural changes. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention)

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12 pages, 3219 KiB

Open AccessArticle

Homeostasis Imbalance of Microglia and Astrocytes Leads to Alteration in the Metabolites of the Kynurenine Pathway in LPS-Induced Depressive-Like Mice

by Xue Tao, Mingzhu Yan, Lisha Wang, Yunfeng Zhou, Zhi Wang, Tianji Xia, Xinmin Liu, Ruile Pan and Qi Chang

Int. J. Mol. Sci. 2020, 21(4), 1460; https://doi.org/10.3390/ijms21041460 - 21 Feb 2020

Cited by 38 | Viewed by 4721

Abstract

In the pathology-oriented study of depression, inflammation hypothesis has received increasing attention for recent years. To mimic the depressive state caused by inflammation, rodents injected intraperitoneally with lipopolysaccharide (LPS) are usually used to stimulate an immune response. However, the dose of LPS that causes depressive-like behavior varies widely across many literatures. Previous study has uncovered the non-linearity in the dose-effect relationship for the depressive-like behavior induced by LPS administration, while the reason for this is still unclear. The present study aims to investigate the underlying mechanisms of this non-linear dose-dependent relationship. Four groups of mice were injected intraperitoneally with different doses of LPS (0, 0.32, 0.8, and 2 mg/kg). The tail suspension test was conducted to evaluate the depressive-like behavior within 23–25 h after the LPS administration. The neuroplasticity was assessed by the levels of related proteins, TrkB and PSD-95, and by the quantification of neurons using Nissl staining. The levels of the two metabolites of the kynurenine (KYN) pathway, 3-hydroxykynurenine (3-HK) and kynurenic acid (KYNA), in the brain were analyzed by LC-MS/MS. Activation of microglia and astrocytes in the brain were also determined by immunohistochemistry and western blotting, respectively. The results showed that, compared with the control group, the mice in the 0.8 mg/kg LPS-treated group exhibited a remarkable increase of immobility time in the tail suspension test. The neuroplasticity of mice in the 0.8 mg/kg LPS-treated group was also significantly reduced. The neurotoxic metabolite, 3-HK, was accumulated significantly in the hippocampus of the 0.8 mg/kg LPS-treated mice. Surprisingly, the 2 mg/kg LPS-treated mice did not exhibit a remarkable change of 3-HK but expressed increased KYNA significantly, which is neuroprotective. Furthermore, the activation of microglia and astrocytes, which were recognized as the primary source of 3-HK and KYNA, respectively, corresponded to the content of these two metabolites of the KYN pathway in each group. Consequently, it was speculated that the homeostasis of different glial cells could lead to a non-linear dose-dependent behavior by regulating the KYN pathway in the LPS-induced depressive-like mice. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention)

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Review

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16 pages, 3197 KiB

Open AccessReview

Migraine: Calcium Channels and Glia

by Marta Kowalska, Michał Prendecki, Thomas Piekut, Wojciech Kozubski and Jolanta Dorszewska

Int. J. Mol. Sci. 2021, 22(5), 2688; https://doi.org/10.3390/ijms22052688 - 7 Mar 2021

Cited by 18 | Viewed by 6803

Abstract

Migraine is a common neurological disease that affects about 11% of the adult population. The disease is divided into two main clinical subtypes: migraine with aura and migraine without aura. According to the neurovascular theory of migraine, the activation of the trigeminovascular system (TGVS) and the release of numerous neuropeptides, including calcitonin gene-related peptide (CGRP) are involved in headache pathogenesis. TGVS can be activated by cortical spreading depression (CSD), a phenomenon responsible for the aura. The mechanism of CSD, stemming in part from aberrant interactions between neurons and glia have been studied in models of familial hemiplegic migraine (FHM), a rare monogenic form of migraine with aura. The present review focuses on those interactions, especially as seen in FHM type 1, a variant of the disease caused by a mutation in CACNA1A, which encodes the α1A subunit of the P/Q-type voltage-gated calcium channel. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention)

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35 pages, 849 KiB

Open AccessReview

Copper Dyshomeostasis in Neurodegenerative Diseases—Therapeutic Implications

by Grażyna Gromadzka, Beata Tarnacka, Anna Flaga and Agata Adamczyk

Int. J. Mol. Sci. 2020, 21(23), 9259; https://doi.org/10.3390/ijms21239259 - 4 Dec 2020

Cited by 169 | Viewed by 11053

Abstract

Copper is one of the most abundant basic transition metals in the human body. It takes part in oxygen metabolism, collagen synthesis, and skin pigmentation, maintaining the integrity of blood vessels, as well as in iron homeostasis, antioxidant defense, and neurotransmitter synthesis. It may also be involved in cell signaling and may participate in modulation of membrane receptor-ligand interactions, control of kinase and related phosphatase functions, as well as many cellular pathways. Its role is also important in controlling gene expression in the nucleus. In the nervous system in particular, copper is involved in myelination, and by modulating synaptic activity as well as excitotoxic cell death and signaling cascades induced by neurotrophic factors, copper is important for various neuronal functions. Current data suggest that both excess copper levels and copper deficiency can be harmful, and careful homeostatic control is important. This knowledge opens up an important new area for potential therapeutic interventions based on copper supplementation or removal in neurodegenerative diseases including Wilson’s disease (WD), Menkes disease (MD), Alzheimer’s disease (AD), Parkinson’s disease (PD), and others. However, much remains to be discovered, in particular, how to regulate copper homeostasis to prevent neurodegeneration, when to chelate copper, and when to supplement it. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention)

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19 pages, 1474 KiB

Open AccessReview

Rethinking Intellectual Disability from Neuro- to Astro-Pathology

by Álvaro Fernández-Blanco and Mara Dierssen

Int. J. Mol. Sci. 2020, 21(23), 9039; https://doi.org/10.3390/ijms21239039 - 27 Nov 2020

Cited by 14 | Viewed by 4256

Abstract

Neurodevelopmental disorders arise from genetic and/or from environmental factors and are characterized by different degrees of intellectual disability. The mechanisms that govern important processes sustaining learning and memory, which are severely affected in intellectual disability, have classically been thought to be exclusively under neuronal control. However, this vision has recently evolved into a more integrative conception in which astroglia, rather than just acting as metabolic supply and structural anchoring for neurons, interact at distinct levels modulating neuronal communication and possibly also cognitive processes. Recently, genetic tools have made it possible to specifically manipulate astrocyte activity unraveling novel functions that involve astrocytes in memory function in the healthy brain. However, astrocyte manipulation has also underscored potential mechanisms by which dysfunctional astrocytes could contribute to memory deficits in several neurodevelopmental disorders revealing new pathogenic mechanisms in intellectual disability. Here, we review the current knowledge about astrocyte dysfunction that might contribute to learning and memory impairment in neurodevelopmental disorders, with special focus on Fragile X syndrome and Down syndrome. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention)

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12 pages, 583 KiB

Open AccessReview

Vesicular Transport of Encapsulated microRNA between Glial and Neuronal Cells

by Walter J. Lukiw and Aileen I. Pogue

Int. J. Mol. Sci. 2020, 21(14), 5078; https://doi.org/10.3390/ijms21145078 - 18 Jul 2020

Cited by 31 | Viewed by 4175

Abstract

Exosomes (EXs) and extracellular microvesicles (EMVs) represent a diverse assortment of plasma membrane-derived nanovesicles, 30–1000 nm in diameter, released by all cell lineages of the central nervous system (CNS). They are examples of a very active and dynamic form of extracellular communication and the conveyance of biological information transfer essential to maintain homeostatic neurological functions and contain complex molecular cargoes representative of the cytoplasm of their cells of origin. These molecular cargoes include various mixtures of proteins, lipids, proteolipids, cytokines, chemokines, carbohydrates, microRNAs (miRNA) and messenger RNAs (mRNA) and other components, including end-stage neurotoxic and pathogenic metabolic products, such as amyloid beta (Aβ) peptides. Brain microglia, for example, respond to both acute CNS injuries and degenerative diseases with complex reactions via the induction of a pro-inflammatory phenotype, and secrete EXs and EMVs enriched in selective pathogenic microRNAs (miRNAs) such as miRNA-34a, miRNA-125b, miRNA-146a, miRNA-155, and others that are known to promote neuro-inflammation, induce complement activation, disrupt innate–immune signaling and deregulate the expression of neuron-specific phosphoproteins involved in neurotropism and synaptic signaling. This communication will review our current understanding of the trafficking of miRNA-containing EXs and EMVs from astrocytes and “activated pro-inflammatory” microglia to target neurons in neurodegenerative diseases with an emphasis on Alzheimer’s disease wherever possible. Full article

(This article belongs to the Special Issue Glial-Neuronal Interactions in Neurological Disorders: Molecular Mechanisms and Potential Points for Intervention)

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