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Synaptic Dysfunction in Health and Disease
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Synaptic Dysfunction in Health and Disease

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 43629

Special Issue Editors

Prof. Flavia Valtorta

E-Mail Website
Guest Editor
IRCCS San Raffaele Scientific Institute, Division of Neuroscience, Vita-Salute San Raffaele University, Milan, Italy
Interests: synaptic vesicles; neurotransmitter release; synapse development; epilepsy; autism spectrum disorders; neuropharmacology
Dr. Jenny Sassone

E-Mail Website
Guest Editor
IRCCS San Raffaele Scientific Institute, Division of Neuroscience, Vita-Salute San Raffaele University, Milan, Italy
Interests: Parkinson's disease; Huntington's disease; neurodegeneration; synapse; glutamate receptor; excitotoxicity; neuropharmacology; dopaminergic neurons

Special Issue Information

Dear Colleagues,

Synapses are highly specialized junction structures that represent the basic units of communication in the brain. Over the last decades, the synapse has been the focus of research efforts that have yielded a body of knowledge about its structure, molecular constituents, and functional properties. The synaptic vesicle was the first cellular organelle to be described in molecular detail, and it is now known that many of its components have an intricate network of interactors. However, much remains to be discovered in many fields of synapse development and plasticity. For instance, the knowledge about the function of silent synapses is still very limited and fragmented; the interplay between mitochondria and synaptic function is unclear. Moreover, emerging studies indicate that autophagy has essential functions at the synapse, but the physiological role of synaptic autophagy is far from being elucidated. Similarly, although the essential role of synaptic plasticity in higher brain functions is acknowledged, much work needs to be done to clarify the molecular bases of plasticity phenomena.

Synapses also have a key role in many brain disorders. Hundreds of mutations in the human synapse proteome (the “synaptome”) have been described and recognized to underlie a plethora of psychiatric and neurological disorders, which are now collectively called “synaptopathies”.

Defects in synapse assembly have been linked to a broad spectrum of neurodevelopmental disorders. In addition, synaptic defects are thought to precede neuronal death in many neurodegenerative diseases, such as Parkinson’s disease, triplet repeat disease, and Alzheimer’s disease. An imbalance between excitatory and inhibitory synaptic signals gives rise to epilepsy. Loss of synaptic homeostasis in specific networks contributes to migraine and to other morbidities characterized by chronic pain, and synaptic dysfunction is an emerging hypothesis explaining affective disorders.

We believe that a better understanding of synaptic physiology and of its dysfunction in disease may drive a transition from a disease classification based on phenomenology to one based on pathophysiological mechanisms. Such a transition will provide novel indications for the development of therapeutic strategies.

This Special Issue of Cells is devoted to all aspects of synapse function in health and disease, both in humans and model organisms. It will contain articles that collectively provide a balanced, state-of-the-art view of synapse biology in health and disease. We seek submissions of high-quality articles on topics that include but are not limited to synapse formation and plasticity, neurotransmitter release, axonal guidance, neuropharmacology, and advanced techniques for studying synapse biology. The submission of articles with breakthrough ideas and hypotheses that move the field forward is encouraged.

Prof. Flavia Valtorta
Dr. Jenny Sassone
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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • neurotransmitters
  • synaptic plasticity
  • synaptic vesicles
  • neuropharmacology
  • neurodegeneration
  • neurodevelopment

Published Papers (10 papers)

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Research

Jump to: Review

13 pages, 2778 KiB  
Article
An Emerging Role of PRRT2 in Regulating Growth Cone Morphology
by Elisa Savino, Fabrizia Claudia Guarnieri, Jin-Wu Tsai, Anna Corradi, Fabio Benfenati and Flavia Valtorta
Cells 2021, 10(10), 2666; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10102666 - 05 Oct 2021
Cited by 3 | Viewed by 2148
Abstract
Mutations in the PRRT2 gene are the main cause for a group of paroxysmal neurological diseases including paroxysmal kinesigenic dyskinesia, episodic ataxia, benign familial infantile seizures, and hemiplegic migraine. In the mature central nervous system, the protein has both a functional and a [...] Read more.
Mutations in the PRRT2 gene are the main cause for a group of paroxysmal neurological diseases including paroxysmal kinesigenic dyskinesia, episodic ataxia, benign familial infantile seizures, and hemiplegic migraine. In the mature central nervous system, the protein has both a functional and a structural role at the synapse. Indeed, PRRT2 participates in the regulation of neurotransmitter release, as well as of actin cytoskeleton dynamics during synaptogenesis. Here, we show a role of the protein also during early stages of neuronal development. We found that PRRT2 accumulates at the growth cone in cultured hippocampal neurons. Overexpression of the protein causes an increase in the size and the morphological complexity of growth cones. In contrast, the growth cones of neurons derived from PRRT2 KO mice are smaller and less elaborated. Finally, we demonstrated that the aberrant shape of PRRT2 KO growth cones is associated with a selective alteration of the growth cone actin cytoskeleton. Our data support a key role of PRRT2 in the regulation of growth cone morphology during neuronal development. Full article
(This article belongs to the Special Issue Synaptic Dysfunction in Health and Disease)
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18 pages, 4055 KiB  
Article
Reduced mGluR5 Activity Modulates Mitochondrial Function
by Miguel A. Gonzalez-Lozano, Joke Wortel, Rolinka J. van der Loo, Jan R. T. van Weering, August B. Smit and Ka Wan Li
Cells 2021, 10(6), 1375; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10061375 - 02 Jun 2021
Cited by 5 | Viewed by 3708
Abstract
The metabotropic glutamate receptor 5 (mGluR5) is an essential modulator of synaptic plasticity, learning and memory; whereas in pathological conditions, it is an acknowledged therapeutic target that has been implicated in multiple brain disorders. Despite robust pre-clinical data, mGluR5 antagonists failed in several [...] Read more.
The metabotropic glutamate receptor 5 (mGluR5) is an essential modulator of synaptic plasticity, learning and memory; whereas in pathological conditions, it is an acknowledged therapeutic target that has been implicated in multiple brain disorders. Despite robust pre-clinical data, mGluR5 antagonists failed in several clinical trials, highlighting the need for a better understanding of the mechanisms underlying mGluR5 function. In this study, we dissected the molecular synaptic modulation mediated by mGluR5 using genetic and pharmacological mouse models to chronically and acutely reduce mGluR5 activity. We found that next to dysregulation of synaptic proteins, the major regulation in protein expression in both models concerned specific processes in mitochondria, such as oxidative phosphorylation. Second, we observed morphological alterations in shape and area of specifically postsynaptic mitochondria in mGluR5 KO synapses using electron microscopy. Third, computational and biochemical assays suggested an increase of mitochondrial function in neurons, with increased level of NADP/H and oxidative damage in mGluR5 KO. Altogether, our observations provide diverse lines of evidence of the modulation of synaptic mitochondrial function by mGluR5. This connection suggests a role for mGluR5 as a mediator between synaptic activity and mitochondrial function, a finding which might be relevant for the improvement of the clinical potential of mGluR5. Full article
(This article belongs to the Special Issue Synaptic Dysfunction in Health and Disease)
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17 pages, 2376 KiB  
Article
Chemical Stimulation of Rodent and Human Cortical Synaptosomes: Implications in Neurodegeneration
by Faraz Ahmad, Yu Jing, Albert Lladó and Ping Liu
Cells 2021, 10(5), 1174; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10051174 - 12 May 2021
Cited by 3 | Viewed by 2881
Abstract
Synaptic plasticity events, including long-term potentiation (LTP), are often regarded as correlates of brain functions of memory and cognition. One of the central players in these plasticity-related phenomena is the α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor (AMPAR). Increased levels of AMPARs on postsynaptic membranes thus constitute a [...] Read more.
Synaptic plasticity events, including long-term potentiation (LTP), are often regarded as correlates of brain functions of memory and cognition. One of the central players in these plasticity-related phenomena is the α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor (AMPAR). Increased levels of AMPARs on postsynaptic membranes thus constitute a biochemical measure of LTP. Isolated synaptic terminals (synaptosomes) are an excellent ex vivo tool to monitor synaptic physiology in healthy and diseased brains, particularly in human research. We herein describe three protocols for chemically-induced LTP (cLTP) in synaptosomes from both rodent and human brain tissues. Two of these chemical stimulation protocols are described for the first time in synaptosomes. A pharmacological block of synaptosomal actin dynamics confirmed the efficiency of the cLTP protocols. Furthermore, the study prototypically evaluated the deficiency of cLTP in cortical synaptosomes obtained from human cases of early-onset Alzheimer’s disease (EOAD) and frontotemporal lobar degeneration (FLTD), as well as an animal model that mimics FLTD. Full article
(This article belongs to the Special Issue Synaptic Dysfunction in Health and Disease)
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13 pages, 2159 KiB  
Article
Role of HMGB1/TLR4 Axis in Ischemia/Reperfusion-Impaired Extracellular Glutamate Clearance in Primary Astrocytes
by Chia-Ho Lin, Han-Yu Chen and Kai-Che Wei
Cells 2020, 9(12), 2585; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9122585 - 03 Dec 2020
Cited by 12 | Viewed by 2462
Abstract
(1) Background: Abnormal accumulation of extracellular glutamate can occur as dysfunction of astrocytic glutamate transporters, which has been linked to ischemic brain injury. Excessive extracellular glutamate-induced abnormal excitotoxicity is the major cause of secondary neuronal damage after cerebral ischemia/reperfusion. However, the definite mechanism [...] Read more.
(1) Background: Abnormal accumulation of extracellular glutamate can occur as dysfunction of astrocytic glutamate transporters, which has been linked to ischemic brain injury. Excessive extracellular glutamate-induced abnormal excitotoxicity is the major cause of secondary neuronal damage after cerebral ischemia/reperfusion. However, the definite mechanism of impaired astrocytic glutamate reuptake remains unclear. (2) Methods: We investigated the mechanism of the HMGB1/TLR4 axis in extracellular glutamate clearance in primary astrocytes exposed to ischemia/reperfusion by using OGD/R (oxygen-glucose deprivation/reoxygenation) model. (3) Results: OGD/R insult activated the HMGB1/TLR4 axis for reducing the activity of glutamate clearance by inhibiting GLAST (glutamate aspartate transporter) expression in primary astrocytes. Interestingly, OGD/R-untreated astrocytes showed impairment of glutamate clearance after exposure to exogenous HMGB1 or conditioned medium from OGD/R-treated astrocytes culture. Inhibition of HMGB1 or TLR4 effectively prevented impaired glutamate clearance, which was induced by OGD/R, exogenous HMGB1, or conditioned medium from OGD/R-treated astrocytes. Furthermore, glycyrrhizic acid attenuated OGD/R-induced impairment of astrocytic glutamate clearance mediated by the HMGB1-TLR4 axis. (4) Conclusion: The HMGB1/TLR4 axis is a potential target for the treatment of post-ischemic excitotoxicity caused by GLAST dysfunction in astrocytes. Full article
(This article belongs to the Special Issue Synaptic Dysfunction in Health and Disease)
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19 pages, 3933 KiB  
Article
Proteomic Characterization of Synaptosomes from Human Substantia Nigra Indicates Altered Mitochondrial Translation in Parkinson’s Disease
by Sarah Plum, Britta Eggers, Stefan Helling, Markus Stepath, Carsten Theiss, Renata E. P. Leite, Mariana Molina, Lea T. Grinberg, Peter Riederer, Manfred Gerlach, Caroline May and Katrin Marcus
Cells 2020, 9(12), 2580; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9122580 - 02 Dec 2020
Cited by 14 | Viewed by 3882
Abstract
The pathological hallmark of Parkinson’s disease (PD) is the loss of neuromelanin-containing dopaminergic neurons within the substantia nigra pars compacta (SNpc). Additionally, numerous studies indicate an altered synaptic function during disease progression. To gain new insights into the molecular processes underlying the alteration [...] Read more.
The pathological hallmark of Parkinson’s disease (PD) is the loss of neuromelanin-containing dopaminergic neurons within the substantia nigra pars compacta (SNpc). Additionally, numerous studies indicate an altered synaptic function during disease progression. To gain new insights into the molecular processes underlying the alteration of synaptic function in PD, a proteomic study was performed. Therefore, synaptosomes were isolated by density gradient centrifugation from SNpc tissue of individuals at advanced PD stages (N = 5) as well as control subjects free of pathology (N = 5) followed by mass spectrometry-based analysis. In total, 362 proteins were identified and assigned to the synaptosomal core proteome. This core proteome comprised all proteins expressed within the synapses without regard to data analysis software, gender, age, or disease. The differential analysis between control subjects and PD cases revealed that CD9 antigen was overrepresented and fourteen proteins, among them Thymidine kinase 2 (TK2), mitochondrial, 39S ribosomal protein L37, neurolysin, and Methionine-tRNA ligase (MARS2) were underrepresented in PD suggesting an alteration in mitochondrial translation within synaptosomes. Full article
(This article belongs to the Special Issue Synaptic Dysfunction in Health and Disease)
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Review

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21 pages, 1570 KiB  
Review
Presynaptic AMPA Receptors in Health and Disease
by Letizia Zanetti, Maria Regoni, Elena Ratti, Flavia Valtorta and Jenny Sassone
Cells 2021, 10(9), 2260; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10092260 - 31 Aug 2021
Cited by 11 | Viewed by 5961
Abstract
AMPA receptors (AMPARs) are ionotropic glutamate receptors that play a major role in excitatory neurotransmission. AMPARs are located at both presynaptic and postsynaptic plasma membranes. A huge number of studies investigated the role of postsynaptic AMPARs in the normal and abnormal functioning of [...] Read more.
AMPA receptors (AMPARs) are ionotropic glutamate receptors that play a major role in excitatory neurotransmission. AMPARs are located at both presynaptic and postsynaptic plasma membranes. A huge number of studies investigated the role of postsynaptic AMPARs in the normal and abnormal functioning of the mammalian central nervous system (CNS). These studies highlighted that changes in the functional properties or abundance of postsynaptic AMPARs are major mechanisms underlying synaptic plasticity phenomena, providing molecular explanations for the processes of learning and memory. Conversely, the role of AMPARs at presynaptic terminals is as yet poorly clarified. Accruing evidence demonstrates that presynaptic AMPARs can modulate the release of various neurotransmitters. Recent studies also suggest that presynaptic AMPARs may possess double ionotropic-metabotropic features and that they are involved in the local regulation of actin dynamics in both dendritic and axonal compartments. In addition, evidence suggests a key role of presynaptic AMPARs in axonal pathology, in regulation of pain transmission and in the physiology of the auditory system. Thus, it appears that presynaptic AMPARs play an important modulatory role in nerve terminal activity, making them attractive as novel pharmacological targets for a variety of pathological conditions. Full article
(This article belongs to the Special Issue Synaptic Dysfunction in Health and Disease)
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22 pages, 1072 KiB  
Review
Role of Nrf2 in Synaptic Plasticity and Memory in Alzheimer’s Disease
by Don A. Davies, Aida Adlimoghaddam and Benedict C. Albensi
Cells 2021, 10(8), 1884; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10081884 - 25 Jul 2021
Cited by 49 | Viewed by 5053
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcription factor that reduces oxidative stress. When reactive oxygen species (ROS) or reactive nitrogen species (RNS) are detected, Nrf2 translocates from the cytoplasm into the nucleus and binds to the antioxidant response element [...] Read more.
Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important transcription factor that reduces oxidative stress. When reactive oxygen species (ROS) or reactive nitrogen species (RNS) are detected, Nrf2 translocates from the cytoplasm into the nucleus and binds to the antioxidant response element (ARE), which regulates the expression of antioxidant and anti-inflammatory genes. Nrf2 impairments are observed in the majority of neurodegenerative disorders, including Alzheimer’s disease (AD). The classic hallmarks of AD include β-amyloid (Aβ) plaques, and neurofibrillary tangles (NFTs). Oxidative stress is observed early in AD and is a novel therapeutic target for the treatment of AD. The nuclear translocation of Nrf2 is impaired in AD compared to controls. Increased oxidative stress is associated with impaired memory and synaptic plasticity. The administration of Nrf2 activators reverses memory and synaptic plasticity impairments in rodent models of AD. Therefore, Nrf2 activators are a potential novel therapeutic for neurodegenerative disorders including AD. Full article
(This article belongs to the Special Issue Synaptic Dysfunction in Health and Disease)
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12 pages, 4164 KiB  
Review
Synapsins and the Synaptic Vesicle Reserve Pool: Floats or Anchors?
by Minchuan Zhang and George J. Augustine
Cells 2021, 10(3), 658; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10030658 - 16 Mar 2021
Cited by 28 | Viewed by 6172
Abstract
In presynaptic terminals, synaptic vesicles (SVs) are found in a discrete cluster that includes a reserve pool that is mobilized during synaptic activity. Synapsins serve as a key protein for maintaining SVs within this reserve pool, but the mechanism that allows synapsins to [...] Read more.
In presynaptic terminals, synaptic vesicles (SVs) are found in a discrete cluster that includes a reserve pool that is mobilized during synaptic activity. Synapsins serve as a key protein for maintaining SVs within this reserve pool, but the mechanism that allows synapsins to do this is unclear. This mechanism is likely to involve synapsins either cross-linking SVs, thereby anchoring SVs to each other, or creating a liquid phase that allows SVs to float within a synapsin droplet. Here, we summarize what is known about the role of synapsins in clustering of SVs and evaluate experimental evidence supporting these two models. Full article
(This article belongs to the Special Issue Synaptic Dysfunction in Health and Disease)
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12 pages, 6187 KiB  
Review
NMDA and AMPA Receptor Autoantibodies in Brain Disorders: From Molecular Mechanisms to Clinical Features
by Fabrizio Gardoni, Jennifer Stanic, Diego Scheggia, Alberto Benussi, Barbara Borroni and Monica Di Luca
Cells 2021, 10(1), 77; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10010077 - 05 Jan 2021
Cited by 20 | Viewed by 4990
Abstract
The role of autoimmunity in central nervous system (CNS) disorders is rapidly expanding. In the last twenty years, different types of autoantibodies targeting subunits of ionotropic glutamate receptors have been found in a variety of patients affected by brain disorders. Several of these [...] Read more.
The role of autoimmunity in central nervous system (CNS) disorders is rapidly expanding. In the last twenty years, different types of autoantibodies targeting subunits of ionotropic glutamate receptors have been found in a variety of patients affected by brain disorders. Several of these antibodies are directed against NMDA receptors (NMDAR), mostly in autoimmune encephalitis, whereas a growing field of research has identified antibodies against AMPA receptor (AMPAR) subunits in patients with different types of epilepsy or frontotemporal dementia. Several in vitro and in vivo studies performed in the last decade have dramatically improved our understanding of the molecular and functional effects induced by both NMDAR and AMPAR autoantibodies at the excitatory glutamatergic synapse and, consequently, their possible role in the onset of clinical symptoms. In particular, the method by which autoantibodies can modulate the localization at synapses of specific target subunits leading to functional impairments and behavioral alterations has been well addressed in animal studies. Overall, these preclinical studies have opened new avenues for the development of novel pharmacological treatments specifically targeting the synaptic activation of ionotropic glutamate receptors. Full article
(This article belongs to the Special Issue Synaptic Dysfunction in Health and Disease)
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22 pages, 1627 KiB  
Review
Right Place at the Right Time: How Changes in Protocadherins Affect Synaptic Connections Contributing to the Etiology of Neurodevelopmental Disorders
by Maria Mancini, Silvia Bassani and Maria Passafaro
Cells 2020, 9(12), 2711; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9122711 - 18 Dec 2020
Cited by 12 | Viewed by 4105
Abstract
During brain development, neurons need to form the correct connections with one another in order to give rise to a functional neuronal circuitry. Mistakes during this process, leading to the formation of improper neuronal connectivity, can result in a number of brain abnormalities [...] Read more.
During brain development, neurons need to form the correct connections with one another in order to give rise to a functional neuronal circuitry. Mistakes during this process, leading to the formation of improper neuronal connectivity, can result in a number of brain abnormalities and impairments collectively referred to as neurodevelopmental disorders. Cell adhesion molecules (CAMs), present on the cell surface, take part in the neurodevelopmental process regulating migration and recognition of specific cells to form functional neuronal assemblies. Among CAMs, the members of the protocadherin (PCDH) group stand out because they are involved in cell adhesion, neurite initiation and outgrowth, axon pathfinding and fasciculation, and synapse formation and stabilization. Given the critical role of these macromolecules in the major neurodevelopmental processes, it is not surprising that clinical and basic research in the past two decades has identified several PCDH genes as responsible for a large fraction of neurodevelopmental disorders. In the present article, we review these findings with a focus on the non-clustered PCDH sub-group, discussing the proteins implicated in the main neurodevelopmental disorders. Full article
(This article belongs to the Special Issue Synaptic Dysfunction in Health and Disease)
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