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Molecular and Cellular Mechanisms in Inflammatory Synaptopathy

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 27426

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Special Issue Editor

Prof. Dr. Georgia Mandolesi

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Guest Editor

1. University of Rome San Raffaele, Via di Val Cannuta, 247 - 00166 Rome, Italy
2. Laboratory of Synaptic Immunopathology, IRCCS San Raffaele Pisana, Via di Val Cannuta, 247 - 00166 Rome, Italy
Interests: synaptic pathology; neurodegeneration; neuroinflammation; multiple sclerosis; experimental autoimmune encephalomyelitis inflammatory cytokines; microrna; excitotoxicity; synaptic plasticity; neuron-glia communication

Special Issue Information

Dear Colleagues,

In the past few years, three emerging concepts from different fields of neuroscience have significantly changed the current knowledge of the pathophysiology of neurological disorders: the concept of synaptic pathology or synaptopathy; the role of inflammation as a key factor influencing both the immature and mature brain; and the dysregulation of molecular mechanisms that drive synaptic transmission and plasticity. As technology has advanced, the ability to study the rich and complex diversity of each of these phenomena in detail has revealed their critical role in several brain pathologies. However, how these events are intermingled and cooperate in triggering or exacerbating neurological disorders is still not well understood.

This Special Issue is dedicated to research articles and reviews on molecular and cellular aspects that link CNS inflammation and synaptic dysfunction and loss in both human and non-human studies. The emphasis will be on neuroinflammatory processes that characterize various neurodegenerative diseases as well as on genetic, epigenetic, and environmental factors contributing to neurodevelopmental disorders.

Prof. Dr. Georgia Mandolesi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

inflammation
neurodegenerative disease
synaptic dysfunction
synaptic loss
synaptic plasticity
neurodevelopmental disorder
cytokines
microglia
astroglia

Published Papers (6 papers)

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Research

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17 pages, 5134 KiB

Open AccessArticle

3,6′-Dithiopomalidomide Ameliorates Hippocampal Neurodegeneration, Microgliosis and Astrogliosis and Improves Cognitive Behaviors in Rats with a Moderate Traumatic Brain Injury

by Pen-Sen Huang, Ping-Yen Tsai, Ling-Yu Yang, Daniela Lecca, Weiming Luo, Dong Seok Kim, Barry J. Hoffer, Yung-Hsiao Chiang, Nigel H. Greig and Jia-Yi Wang

Int. J. Mol. Sci. 2021, 22(15), 8276; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158276 - 31 Jul 2021

Cited by 9 | Viewed by 4038

Abstract

Traumatic brain injury (TBI) is a leading cause of disability and mortality worldwide. It can instigate immediate cell death, followed by a time-dependent secondary injury that results from disproportionate microglial and astrocyte activation, excessive inflammation and oxidative stress in brain tissue, culminating in both short- and long-term cognitive dysfunction and behavioral deficits. Within the brain, the hippocampus is particularly vulnerable to a TBI. We studied a new pomalidomide (Pom) analog, namely, 3,6′-dithioPom (DP), and Pom as immunomodulatory imide drugs (IMiD) for mitigating TBI-induced hippocampal neurodegeneration, microgliosis, astrogliosis and behavioral impairments in a controlled cortical impact (CCI) model of TBI in rats. Both agents were administered as a single intravenous dose (0.5 mg/kg) at 5 h post injury so that the efficacies could be compared. Pom and DP significantly reduced the contusion volume evaluated at 24 h and 7 days post injury. Both agents ameliorated short-term memory deficits and anxiety behavior at 7 days after a TBI. The number of degenerating neurons in the CA1 and dentate gyrus (DG) regions of the hippocampus after a TBI was reduced by Pom and DP. DP, but not Pom, significantly attenuated the TBI-induced microgliosis and DP was more efficacious than Pom at attenuating the TBI-induced astrogliosis in CA1 and DG at 7D after a TBI. In summary, a single intravenous injection of Pom or DP, given 5 h post TBI, significantly reduced hippocampal neurodegeneration and prevented cognitive deficits with a concomitant attenuation of the neuroinflammation in the hippocampus. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms in Inflammatory Synaptopathy)

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Review

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20 pages, 1460 KiB

Open AccessReview

Synaptic Dysfunction in Multiple Sclerosis: A Red Thread from Inflammation to Network Disconnection

by Laura Bellingacci, Andrea Mancini, Lorenzo Gaetani, Alessandro Tozzi, Lucilla Parnetti and Massimiliano Di Filippo

Int. J. Mol. Sci. 2021, 22(18), 9753; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189753 - 09 Sep 2021

Cited by 16 | Viewed by 3083

Abstract

Multiple sclerosis (MS) has been clinically considered a chronic inflammatory disease of the white matter; however, in the last decade growing evidence supported an important role of gray matter pathology as a major contributor of MS-related disability and the involvement of synaptic structures assumed a key role in the pathophysiology of the disease. Synaptic contacts are considered central units in the information flow, involved in synaptic transmission and plasticity, critical processes for the shaping and functioning of brain networks. During the course of MS, the immune system and its diffusible mediators interact with synaptic structures leading to changes in their structure and function, influencing brain network dynamics. The purpose of this review is to provide an overview of the existing literature on synaptic involvement during experimental and human MS, in order to understand the mechanisms by which synaptic failure eventually leads to brain networks alterations and contributes to disabling MS symptoms and disease progression. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms in Inflammatory Synaptopathy)

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17 pages, 1224 KiB

Open AccessReview

Microglia and the Aging Brain: Are Geriatric Microglia Linked to Poor Sleep Quality?

by Mohammed E. Choudhury, Kazuya Miyanishi, Haruna Takeda and Junya Tanaka

Int. J. Mol. Sci. 2021, 22(15), 7824; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157824 - 22 Jul 2021

Cited by 9 | Viewed by 3436

Abstract

Poor sleep quality and disrupted circadian behavior are a normal part of aging and include excessive daytime sleepiness, increased sleep fragmentation, and decreased total sleep time and sleep quality. Although the neuronal decline underlying the cellular mechanism of poor sleep has been extensively investigated, brain function is not fully dependent on neurons. A recent antemortem autographic study and postmortem RNA sequencing and immunohistochemical studies on aged human brain have investigated the relationship between sleep fragmentation and activation of the innate immune cells of the brain, microglia. In the process of aging, there are marked reductions in the number of brain microglial cells, and the depletion of microglial cells disrupts circadian rhythmicity of brain tissue. We also showed, in a previous study, that pharmacological suppression of microglial function induced sleep abnormalities. However, the mechanism underlying the contribution of microglial cells to sleep homeostasis is only beginning to be understood. This review revisits the impact of aging on the microglial population and activation, as well as microglial contribution to sleep maintenance and response to sleep loss. Most importantly, this review will answer questions such as whether there is any link between senescent microglia and age-related poor quality sleep and how this exacerbates neurodegenerative disease. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms in Inflammatory Synaptopathy)

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18 pages, 1425 KiB

Open AccessReview

Neuroinflammation: A Signature or a Cause of Epilepsy?

by Enrico Pracucci, Vinoshene Pillai, Didi Lamers, Riccardo Parra and Silvia Landi

Int. J. Mol. Sci. 2021, 22(13), 6981; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136981 - 29 Jun 2021

Cited by 38 | Viewed by 5249

Abstract

Epilepsy can be both a primary pathology and a secondary effect of many neurological conditions. Many papers show that neuroinflammation is a product of epilepsy, and that in pathological conditions characterized by neuroinflammation, there is a higher probability to develop epilepsy. However, the bidirectional mechanism of the reciprocal interaction between epilepsy and neuroinflammation remains to be fully understood. Here, we attempt to explore and discuss the relationship between epilepsy and inflammation in some paradigmatic neurological and systemic disorders associated with epilepsy. In particular, we have chosen one representative form of epilepsy for each one of its actual known etiologies. A better understanding of the mechanistic link between neuroinflammation and epilepsy would be important to improve subject-based therapies, both for prophylaxis and for the treatment of epilepsy. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms in Inflammatory Synaptopathy)

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17 pages, 1005 KiB

Open AccessReview

Alpha-Synuclein as a Prominent Actor in the Inflammatory Synaptopathy of Parkinson’s Disease

by Antonella Cardinale, Valeria Calabrese, Antonio de Iure and Barbara Picconi

Int. J. Mol. Sci. 2021, 22(12), 6517; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126517 - 17 Jun 2021

Cited by 35 | Viewed by 4724

Abstract

Parkinson’s disease (PD) is considered the most common disorder of synucleinopathy, which is characterised by intracellular inclusions of aggregated and misfolded α-synuclein (α-syn) protein in various brain regions, and the loss of dopaminergic neurons. During the early prodromal phase of PD, synaptic alterations happen before cell death, which is linked to the synaptic accumulation of toxic α-syn specifically in the presynaptic terminals, affecting neurotransmitter release. The oligomers and protofibrils of α-syn are the most toxic species, and their overexpression impairs the distribution and activation of synaptic proteins, such as the SNARE complex, preventing neurotransmitter exocytosis and neuronal synaptic communication. In the last few years, the role of the immune system in PD has been increasingly considered. Microglial and astrocyte activation, the gene expression of proinflammatory factors, and the infiltration of immune cells from the periphery to the central nervous system (CNS) represent the main features of the inflammatory response. One of the actors of these processes is α-syn accumulation. In light of this, here, we provide a systematic review of PD-related α-syn and inflammation inter-players. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms in Inflammatory Synaptopathy)

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35 pages, 2538 KiB

Open AccessReview

Neuroprotective and Immunomodulatory Action of the Endocannabinoid System under Neuroinflammation

by Ludmila A. Kasatkina, Sonja Rittchen and Eva M. Sturm

Int. J. Mol. Sci. 2021, 22(11), 5431; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115431 - 21 May 2021

Cited by 46 | Viewed by 6036

Abstract

Endocannabinoids (eCBs) are lipid-based retrograde messengers with a relatively short half-life that are produced endogenously and, upon binding to the primary cannabinoid receptors CB_1/2, mediate multiple mechanisms of intercellular communication within the body. Endocannabinoid signaling is implicated in brain development, memory formation, learning, mood, anxiety, depression, feeding behavior, analgesia, and drug addiction. It is now recognized that the endocannabinoid system mediates not only neuronal communications but also governs the crosstalk between neurons, glia, and immune cells, and thus represents an important player within the neuroimmune interface. Generation of primary endocannabinoids is accompanied by the production of their congeners, the N-acylethanolamines (NAEs), which together with N-acylneurotransmitters, lipoamino acids and primary fatty acid amides comprise expanded endocannabinoid/endovanilloid signaling systems. Most of these compounds do not bind CB_1/2, but signal via several other pathways involving the transient receptor potential cation channel subfamily V member 1 (TRPV1), peroxisome proliferator-activated receptor (PPAR)-α and non-cannabinoid G-protein coupled receptors (GPRs) to mediate anti-inflammatory, immunomodulatory and neuroprotective activities. In vivo generation of the cannabinoid compounds is triggered by physiological and pathological stimuli and, specifically in the brain, mediates fine regulation of synaptic strength, neuroprotection, and resolution of neuroinflammation. Here, we review the role of the endocannabinoid system in intrinsic neuroprotective mechanisms and its therapeutic potential for the treatment of neuroinflammation and associated synaptopathy. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms in Inflammatory Synaptopathy)

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