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Synaptic Vulnerability: From Biological to Therapeutic Point of View

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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 (15 June 2023) | Viewed by 8355

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Special Issue Editors

Dr. Mattia Volta

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Guest Editor

Institute for Biomedicine, Eurac Research-Affiliated Institute of the University of Lübeck, 39100 Bolzano, Italy
Interests: LRRK2; Parkinson’s disease; autophagy; synapse; alpha-synuclein
Special Issues, Collections and Topics in MDPI journals

Dr. Gaia Faustini

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Guest Editor

Division of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy
Interests: alpha-synuclein; Parkinson’s disease; neurodegeneration; synapsins

Special Issue Information

Dear Colleagues,

The synapse plays a critical role in all phases of neuronal life. Neurotransmission, synaptic plasticity, and neuron development are crucial for synaptic maintenance and vesicle turnover, contributing to synapse organization, the mobilization of synaptic vesicles, and neurotransmitter release.

Events underlying synapse formation, plasticity, and neurotransmission are thus essential and synaptic plasticity changes, neurotransmission disruption, synaptic protein alterations, receptor dysregulation as well as mitochondrial alterations may increase synaptic vulnerability, inhibiting the proper turnover and clustering of synaptic vesicles and ultimately leading to neuronal death. Neurons are particularly vulnerable to internal and external factors, which may cause injury followed by neurodegeneration. Different insults may increase synaptic vulnerability, disrupting homeostatic equilibrium and resulting in the progression of the pathology.

This Special Issue aims to cover the biological aspects of the synapse, from neuronal development to mature synapse. Descriptions of molecular mechanisms are welcome to underline synaptic physiological homeostasis as well as the disruption of synaptic machinery and the onset of neurodegenerative disorders.

Manuscripts describing recent developments of treatments for delaying or preventing neuronal injury are essential to understanding the novel therapeutic approaches underpinning the molecular events of synaptic injury and vulnerability and delaying the onset or progression of neuronal loss.

Dr. Mattia Volta
Dr. Gaia Faustini
Guest Editors

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

synaptic vesicles
vesicle turnover
neurotransmitter release
excitability
neurodegeneration
mitochondrial deficit
synaptic homeostasis
cognitive deficit
Parkinson’s disease
Alzheimer’s disease
epilepsy

Published Papers (4 papers)

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Research

19 pages, 9864 KiB

Open AccessArticle

Changes in α-Synuclein Posttranslational Modifications in an AAV-Based Mouse Model of Parkinson’s Disease

by Viviana Brembati, Gaia Faustini, Francesca Longhena, Tiago Fleming Outeiro and Arianna Bellucci

Int. J. Mol. Sci. 2023, 24(17), 13435; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241713435 - 30 Aug 2023

Cited by 2 | Viewed by 1264

Abstract

Parkinson’s disease (PD) pathology is characterized by the loss of dopaminergic neurons of the nigrostriatal system and accumulation of Lewy bodies (LB) and Lewy neurites (LN), inclusions mainly composed of alpha-synuclein (α-Syn) fibrils. Studies linking the occurrence of mutations and multiplications of the α-Syn gene (SNCA) to the onset of PD support that α-Syn deposition may play a causal role in the disease, in line with the hypothesis that disease progression may correlate with the spreading of LB pathology in the brain. Interestingly, LB accumulate posttranslationally modified forms of α-Syn, suggesting that α-Syn posttranslational modifications impinge on α-Syn aggregation and/or toxicity. Here, we aimed at investigating changes in α-Syn phosphorylation, nitration and acetylation in mice subjected to nigral stereotaxic injections of adeno-associated viral vectors inducing overexpression of human α-Syn (AAV-hα-Syn), that model genetic PD with SNCA multiplications. We detected a mild increase of serine (Ser) 129 phosphorylated α-Syn in the substantia nigra (SN) of AAV-hα-Syn-injected mice in spite of the previously described marked accumulation of this PTM in the striatum. Following AAV-hα-Syn injection, tyrosine (Tyr) 125/136 nitrated α-Syn accumulation in the absence of general 3-nitrotirosine (3NT) or nitrated-Tyr39 α-Syn changes and augmented protein acetylation abundantly overlapping with α-Syn immunopositivity were also detected. Full article

(This article belongs to the Special Issue Synaptic Vulnerability: From Biological to Therapeutic Point of View)

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13 pages, 2173 KiB

Open AccessArticle

Neurosteroids Mediate Neuroprotection in an In Vitro Model of Hypoxic/Hypoglycaemic Excitotoxicity via δ-GABA_A Receptors without Affecting Synaptic Plasticity

by Xènia Puig-Bosch, Markus Ballmann, Stefan Bieletzki, Bernd Antkowiak, Uwe Rudolph, Hanns Ulrich Zeilhofer and Gerhard Rammes

Int. J. Mol. Sci. 2023, 24(10), 9056; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24109056 - 21 May 2023

Cited by 1 | Viewed by 1485

Abstract

Neurosteroids and benzodiazepines are modulators of the GABA_A receptors, thereby causing anxiolysis. Furthermore, benzodiazepines such as midazolam are known to cause adverse side-effects on cognition upon administration. We previously found that midazolam at nanomolar concentrations (10 nM) blocked long-term potentiation (LTP). Here, we aim to study the effect of neurosteroids and their synthesis using XBD173, which is a synthetic compound that promotes neurosteroidogenesis by binding to the translocator protein 18 kDa (TSPO), since they might provide anxiolytic activity with a favourable side-effect profile. By means of electrophysiological measurements and the use of mice with targeted genetic mutations, we revealed that XBD173, a selective ligand of the translocator protein 18 kDa (TSPO), induced neurosteroidogenesis. In addition, the exogenous application of potentially synthesised neurosteroids (THDOC and allopregnanolone) did not depress hippocampal CA1-LTP, the cellular correlate of learning and memory. This phenomenon was observed at the same concentrations that neurosteroids conferred neuroprotection in a model of ischaemia-induced hippocampal excitotoxicity. In conclusion, our results indicate that TSPO ligands are promising candidates for post-ischaemic recovery exerting neuroprotection, in contrast to midazolam, without detrimental effects on synaptic plasticity. Full article

(This article belongs to the Special Issue Synaptic Vulnerability: From Biological to Therapeutic Point of View)

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30 pages, 14303 KiB

Open AccessArticle

Phospholipase D1 Attenuation Therapeutics Promotes Resilience against Synaptotoxicity in 12-Month-Old 3xTg-AD Mouse Model of Progressive Neurodegeneration

by Chandramouli Natarajan, Charles Cook, Karthik Ramaswamy and Balaji Krishnan

Int. J. Mol. Sci. 2023, 24(4), 3372; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043372 - 08 Feb 2023

Cited by 1 | Viewed by 2290

Abstract

Abrogating synaptotoxicity in age-related neurodegenerative disorders is an extremely promising area of research with significant neurotherapeutic implications in tauopathies including Alzheimer’s disease (AD). Our studies using human clinical samples and mouse models demonstrated that aberrantly elevated phospholipase D1 (PLD1) is associated with amyloid beta (Aβ) and tau-driven synaptic dysfunction and underlying memory deficits. While knocking out the lipolytic PLD1 gene is not detrimental to survival across species, elevated expression is implicated in cancer, cardiovascular conditions and neuropathologies, leading to the successful development of well-tolerated mammalian PLD isoform-specific small molecule inhibitors. Here, we address the importance of PLD1 attenuation, achieved using repeated 1 mg/kg of VU0155069 (VU01) intraperitoneally every alternate day for a month in 3xTg-AD mice beginning only from ~11 months of age (with greater influence of tau-driven insults) compared to age-matched vehicle (0.9% saline)-injected siblings. A multimodal approach involving behavior, electrophysiology and biochemistry corroborate the impact of this pre-clinical therapeutic intervention. VU01 proved efficacious in preventing in later stage AD-like cognitive decline affecting perirhinal cortex-, hippocampal- and amygdala-dependent behaviors. Glutamate-dependent HFS-LTP and LFS-LTD improved. Dendritic spine morphology showed the preservation of mushroom and filamentous spine characteristics. Differential PLD1 immunofluorescence and co-localization with Aβ were noted. Full article

(This article belongs to the Special Issue Synaptic Vulnerability: From Biological to Therapeutic Point of View)

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20 pages, 2045 KiB

Open AccessArticle

Methylphenidate Restores Behavioral and Neuroplasticity Impairments in the Prenatal Nicotine Exposure Mouse Model of ADHD: Evidence for Involvement of AMPA Receptor Subunit Composition and Synaptic Spine Morphology in the Hippocampus

by Darwin Contreras, Ricardo Piña, Claudia Carvallo, Felipe Godoy, Gonzalo Ugarte, Marc Zeise, Carlos Rozas and Bernardo Morales

Int. J. Mol. Sci. 2022, 23(13), 7099; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137099 - 26 Jun 2022

Cited by 4 | Viewed by 2697

Abstract

In ADHD treatment, methylphenidate (MPH) is the most frequently used medication. The present work provides evidence that MPH restored behavioral impairments and neuroplasticity due to changes in AMPAR subunit composition and distribution, as well as maturation of dendritic spines, in a prenatal nicotine exposure (PNE) ADHD mouse model. PNE animals and controls were given a single oral dose of MPH (1 mg/kg), and their behavior was tested for attention, hyperactivity, and working memory. Long-term potentiation (LTP) was induced and analyzed at the CA3/CA1 synapse in hippocampal slices taken from the same animals tested behaviorally, measuring fEPSPs and whole-cell patch-clamp EPSCs. By applying crosslinking and Western blots, we estimated the LTP effects on AMPAR subunit composition and distribution. The density and types of dendritic spines were quantified by using the Golgi staining method. MPH completely restored the behavioral impairments of PNE mice. Reduced LTP and AMPA-receptor-mediated EPSCs were also restored. EPSC amplitudes were tightly correlated with numbers of GluA1/GluA1 AMPA receptors at the cell surface. Finally, we found a lower density of dendritic spines in hippocampal pyramidal neurons in PNE mice, with a higher fraction of thin-type immature spines and a lower fraction of mushroom mature spines; the latter effect was also reversed by MPH. Full article

(This article belongs to the Special Issue Synaptic Vulnerability: From Biological to Therapeutic Point of View)

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