International Journal of Molecular Sciences

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4 pages, 176 KiB

Open AccessEditorial

Molecular Mechanisms of Synaptic Plasticity: Dynamic Changes in Neuron Functions

by Giuseppina Martella

Int. J. Mol. Sci. 2023, 24(16), 12567; https://doi.org/10.3390/ijms241612567 - 8 Aug 2023

Cited by 1 | Viewed by 1543

Abstract

The human brain has hundreds of billions of neurons and at least 7 million dendrites have been hypothesized to exist for each neuron, with over 100 trillion neuron–neuron, neuron–muscle, and neuron–endocrine cell synapses [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity: Dynamic Changes in Neurons Functions)

Research

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17 pages, 18709 KiB

Open AccessArticle

Visualizing the Synaptic and Cellular Ultrastructure in Neurons Differentiated from Human Induced Neural Stem Cells—An Optimized Protocol

by Philipp Capetian, Lorenz Müller, Jens Volkmann, Manfred Heckmann, Süleyman Ergün and Nicole Wagner

Int. J. Mol. Sci. 2020, 21(5), 1708; https://doi.org/10.3390/ijms21051708 - 2 Mar 2020

Cited by 6 | Viewed by 6432

Abstract

The size of the synaptic subcomponents falls below the limits of visible light microscopy. Despite new developments in advanced microscopy techniques, the resolution of transmission electron microscopy (TEM) remains unsurpassed. The requirements of tissue preservation are very high, and human post mortem material [...] Read more.

The size of the synaptic subcomponents falls below the limits of visible light microscopy. Despite new developments in advanced microscopy techniques, the resolution of transmission electron microscopy (TEM) remains unsurpassed. The requirements of tissue preservation are very high, and human post mortem material often does not offer adequate quality. However, new reprogramming techniques that generate human neurons in vitro provide samples that can easily fulfill these requirements. The objective of this study was to identify the culture technique with the best ultrastructural preservation in combination with the best embedding and contrasting technique for visualizing neuronal elements. Two induced neural stem cell lines derived from healthy control subjects underwent differentiation either adherent on glass coverslips, embedded in a droplet of highly concentrated Matrigel, or as a compact neurosphere. Afterward, they were fixed using a combination of glutaraldehyde (GA) and paraformaldehyde (PFA) followed by three approaches (standard stain, Ruthenium red stain, high contrast en-bloc stain) using different combinations of membrane enhancing and contrasting steps before ultrathin sectioning and imaging by TEM. The compact free-floating neurospheres exhibited the best ultrastructural preservation. High-contrast en-bloc stain offered particularly sharp staining of membrane structures and the highest quality visualization of neuronal structures. In conclusion, compact neurospheres growing under free-floating conditions in combination with a high contrast en-bloc staining protocol, offer the optimal preservation and contrast with a particular focus on visualizing membrane structures as required for analyzing synaptic structures. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity: Dynamic Changes in Neurons Functions)

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18 pages, 3308 KiB

Open AccessArticle

Developmental Time Course of SNAP-25 Isoforms Regulate Hippocampal Long-Term Synaptic Plasticity and Hippocampus-Dependent Learning

by Katisha R. Gopaul, Muhammad Irfan, Omid Miry, Linnea R. Vose, Alexander Moghadam, Galadu Subah, Tomas Hökfelt, Christina Bark and Patric K. Stanton

Int. J. Mol. Sci. 2020, 21(4), 1448; https://doi.org/10.3390/ijms21041448 - 20 Feb 2020

Cited by 11 | Viewed by 3524

Abstract

SNAP-25 is essential to activity-dependent vesicle fusion and neurotransmitter release in the nervous system. During early development and adulthood, SNAP-25 appears to have differential influences on short- and long-term synaptic plasticity. The involvement of SNAP-25 in these processes may be different at hippocampal [...] Read more.

SNAP-25 is essential to activity-dependent vesicle fusion and neurotransmitter release in the nervous system. During early development and adulthood, SNAP-25 appears to have differential influences on short- and long-term synaptic plasticity. The involvement of SNAP-25 in these processes may be different at hippocampal and neocortical synapses because of the presence of two different splice variants, which are developmentally regulated. We show here that the isoform SNAP-25a, which is expressed first developmentally in rodent brain, contributes to developmental regulation of the expression of both long-term depression (LTD) and long-term potentiation (LTP) at Schaffer collateral-CA1 synapses in the hippocampus. In one month old mice lacking the developmentally later expressed isoform SNAP-25b, Schaffer collateral-CA1 synapses showed faster release kinetics, decreased LTP and enhanced LTD. By four months of age, SNAP-25b-deficient mice appeared to have compensated for the lack of the adult SNAP-25b isoform, now exhibiting larger LTP and no differences in LTD compared to wild type mice. Interestingly, learning a hippocampus-dependent task reversed the reductions in LTP, but not LTD, seen at one month of age. In four month old adult mice, learning prevented the compensatory up-regulation of LTD that we observed prior to training. These findings support the hypothesis that SNAP-25b promotes stronger LTP and weakens LTD at Schaffer collateral-CA1 synapses in young mice, and suggest that compensatory mechanisms can reverse alterations in synaptic plasticity associated with a lack of SNAP-25b, once mice reach adulthood. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity: Dynamic Changes in Neurons Functions)

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12 pages, 5375 KiB

Open AccessArticle

Dystonia: Sparse Synapses for D2 Receptors in Striatum of a DYT1 Knock-out Mouse Model

by Vincenza D’Angelo, Emanuela Paldino, Silvia Cardarelli, Roberto Sorge, Francesca Romana Fusco, Stefano Biagioni, Nicola Biagio Mercuri, Mauro Giorgi and Giuseppe Sancesario

Int. J. Mol. Sci. 2020, 21(3), 1073; https://doi.org/10.3390/ijms21031073 - 6 Feb 2020

Cited by 5 | Viewed by 3330

Abstract

Dystonia pathophysiology has been partly linked to downregulation and dysfunction of dopamine D2 receptors in striatum. We aimed to investigate the possible morpho-structural correlates of D2 receptor downregulation in the striatum of a DYT1 Tor1a mouse model. Adult control Tor1a+/+ and mutant Tor1a+/− [...] Read more.

Dystonia pathophysiology has been partly linked to downregulation and dysfunction of dopamine D2 receptors in striatum. We aimed to investigate the possible morpho-structural correlates of D2 receptor downregulation in the striatum of a DYT1 Tor1a mouse model. Adult control Tor1a+/+ and mutant Tor1a+/− mice were used. The brains were perfused and free-floating sections of basal ganglia were incubated with polyclonal anti-D2 antibody, followed by secondary immune-fluorescent antibody. Confocal microscopy was used to detect immune-fluorescent signals. The same primary antibody was used to evaluate D2 receptor expression by western blot. The D2 receptor immune-fluorescence appeared circumscribed in small disks (~0.3–0.5 µm diameter), likely representing D2 synapse aggregates, densely distributed in the striatum of Tor1a+/+ mice. In the Tor1a+/− mice the D2 aggregates were significantly smaller (µm² 2.4 ± SE 0.16, compared to µm² 6.73 ± SE 3.41 in Tor1a+/+) and sparse, with ~30% less number per microscopic field, value correspondent to the amount of reduced D2 expression in western blotting analysis. In DYT1 mutant mice the sparse and small D2 synapses in the striatum may be insufficient to “gate” the amount of presynaptic dopamine release diffusing in peri-synaptic space, and this consequently may result in a timing and spatially larger nonselective sphere of influence of dopamine action. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity: Dynamic Changes in Neurons Functions)

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20 pages, 2642 KiB

Open AccessArticle

CB₁ Activity Drives the Selection of Navigational Strategies: A Behavioral and c-Fos Immunoreactivity Study

by Daniela Laricchiuta, Francesca Balsamo, Carlo Fabrizio, Anna Panuccio, Andrea Termine and Laura Petrosini

Int. J. Mol. Sci. 2020, 21(3), 1072; https://doi.org/10.3390/ijms21031072 - 6 Feb 2020

Cited by 5 | Viewed by 3120

Abstract

To promote efficient explorative behaviors, subjects adaptively select spatial navigational strategies based on landmarks or a cognitive map. The hippocampus works alone or in conjunction with the dorsal striatum, both representing the neuronal underpinnings of the navigational strategies organized on the basis of [...] Read more.

To promote efficient explorative behaviors, subjects adaptively select spatial navigational strategies based on landmarks or a cognitive map. The hippocampus works alone or in conjunction with the dorsal striatum, both representing the neuronal underpinnings of the navigational strategies organized on the basis of different systems of spatial coordinate integration. The high expression of cannabinoid type 1 (CB₁) receptors in structures related to spatial learning—such as the hippocampus, dorsal striatum and amygdala—renders the endocannabinoid system a critical target to study the balance between landmark- and cognitive map-based navigational strategies. In the present study, mice treated with the CB₁-inverse agonist/antagonist AM251 or vehicle were trained on a Circular Hole Board, a task that could be solved through either navigational strategy. At the end of the behavioral testing, c-Fos immunoreactivity was evaluated in specific nuclei of the hippocampus, dorsal striatum and amygdala. AM251 treatment impaired spatial learning and modified the pattern of the performed navigational strategies as well as the c-Fos immunoreactivity in the hippocampus, dorsal striatum and amygdala. The present findings shed light on the involvement of CB₁ receptors as part of the selection system of the navigational strategies implemented to efficiently solve the spatial problem. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity: Dynamic Changes in Neurons Functions)

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19 pages, 2336 KiB

Open AccessArticle

Loss of Non-Apoptotic Role of Caspase-3 in the PINK1 Mouse Model of Parkinson’s Disease

by Paola Imbriani, Annalisa Tassone, Maria Meringolo, Giulia Ponterio, Graziella Madeo, Antonio Pisani, Paola Bonsi and Giuseppina Martella

Int. J. Mol. Sci. 2019, 20(14), 3407; https://doi.org/10.3390/ijms20143407 - 11 Jul 2019

Cited by 21 | Viewed by 4008

Abstract

Caspases are a family of conserved cysteine proteases that play key roles in multiple cellular processes, including programmed cell death and inflammation. Recent evidence shows that caspases are also involved in crucial non-apoptotic functions, such as dendrite development, axon pruning, and synaptic plasticity [...] Read more.

Caspases are a family of conserved cysteine proteases that play key roles in multiple cellular processes, including programmed cell death and inflammation. Recent evidence shows that caspases are also involved in crucial non-apoptotic functions, such as dendrite development, axon pruning, and synaptic plasticity mechanisms underlying learning and memory processes. The activated form of caspase-3, which is known to trigger widespread damage and degeneration, can also modulate synaptic function in the adult brain. Thus, in the present study, we tested the hypothesis that caspase-3 modulates synaptic plasticity at corticostriatal synapses in the phosphatase and tensin homolog (PTEN) induced kinase 1 (PINK1) mouse model of Parkinson’s disease (PD). Loss of PINK1 has been previously associated with an impairment of corticostriatal long-term depression (LTD), rescued by amphetamine-induced dopamine release. Here, we show that caspase-3 activity, measured after LTD induction, is significantly decreased in the PINK1 knockout model compared with wild-type mice. Accordingly, pretreatment of striatal slices with the caspase-3 activator α-(Trichloromethyl)-4-pyridineethanol (PETCM) rescues a physiological LTD in PINK1 knockout mice. Furthermore, the inhibition of caspase-3 prevents the amphetamine-induced rescue of LTD in the same model. Our data support a hormesis-based double role of caspase-3; when massively activated, it induces apoptosis, while at lower level of activation, it modulates physiological phenomena, like the expression of corticostriatal LTD. Exploring the non-apoptotic activation of caspase-3 may contribute to clarify the mechanisms involved in synaptic failure in PD, as well as in view of new potential pharmacological targets. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity: Dynamic Changes in Neurons Functions)

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17 pages, 1988 KiB

Open AccessArticle

Corticosterone Upregulates Gene and Protein Expression of Catecholamine Markers in Organotypic Brainstem Cultures

by Carla L. Busceti, Rosangela Ferese, Domenico Bucci, Larisa Ryskalin, Stefano Gambardella, Michele Madonna, Ferdinando Nicoletti and Francesco Fornai

Int. J. Mol. Sci. 2019, 20(12), 2901; https://doi.org/10.3390/ijms20122901 - 14 Jun 2019

Cited by 10 | Viewed by 3186

Abstract

Glucocorticoids are produced by the adrenal cortex and regulate cell metabolism in a variety of organs. This occurs either directly, by acting on specific receptors in a variety of cells, or by stimulating catecholamine expression within neighbor cells of the adrenal medulla. In [...] Read more.

Glucocorticoids are produced by the adrenal cortex and regulate cell metabolism in a variety of organs. This occurs either directly, by acting on specific receptors in a variety of cells, or by stimulating catecholamine expression within neighbor cells of the adrenal medulla. In this way, the whole adrenal gland may support specific metabolic requirements to cope with stressful conditions from external environment or internal organs. In addition, glucocorticoid levels may increase significantly in the presence of inappropriate secretion from adrenal cortex or may be administered at high doses to treat inflammatory disorders. In these conditions, metabolic alterations and increased blood pressure may occur, although altered sleep-waking cycle, anxiety, and mood disorders are frequent. These latter symptoms remain unexplained at the molecular level, although they overlap remarkably with disorders affecting catecholamine nuclei of the brainstem reticular formation. In fact, the present study indicates that various doses of glucocorticoids alter the expression of genes and proteins, which are specific for reticular catecholamine neurons. In detail, corticosterone administration to organotypic mouse brainstem cultures significantly increases Tyrosine hydroxylase (TH) and Dopamine transporter (DAT), while Phenylethanolamine N-methyltransferase (PNMT) is not affected. On the other hand, Dopamine Beta-Hydroxylase (DBH) increases only after very high doses of corticosterone. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity: Dynamic Changes in Neurons Functions)

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Review

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20 pages, 1248 KiB

Open AccessReview

Inhibitory Plasticity: From Molecules to Computation and Beyond

by Daniela Gandolfi, Albertino Bigiani, Carlo Adolfo Porro and Jonathan Mapelli

Int. J. Mol. Sci. 2020, 21(5), 1805; https://doi.org/10.3390/ijms21051805 - 6 Mar 2020

Cited by 18 | Viewed by 7459

Abstract

Synaptic plasticity is the cellular and molecular counterpart of learning and memory and, since its first discovery, the analysis of the mechanisms underlying long-term changes of synaptic strength has been almost exclusively focused on excitatory connections. Conversely, inhibition was considered as a fixed [...] Read more.

Synaptic plasticity is the cellular and molecular counterpart of learning and memory and, since its first discovery, the analysis of the mechanisms underlying long-term changes of synaptic strength has been almost exclusively focused on excitatory connections. Conversely, inhibition was considered as a fixed controller of circuit excitability. Only recently, inhibitory networks were shown to be finely regulated by a wide number of mechanisms residing in their synaptic connections. Here, we review recent findings on the forms of inhibitory plasticity (IP) that have been discovered and characterized in different brain areas. In particular, we focus our attention on the molecular pathways involved in the induction and expression mechanisms leading to changes in synaptic efficacy, and we discuss, from the computational perspective, how IP can contribute to the emergence of functional properties of brain circuits. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity: Dynamic Changes in Neurons Functions)

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25 pages, 1296 KiB

Open AccessReview

Neurons, Glia, Extracellular Matrix and Neurovascular Unit: A Systems Biology Approach to the Complexity of Synaptic Plasticity in Health and Disease

by Ciro De Luca, Anna Maria Colangelo, Assunta Virtuoso, Lilia Alberghina and Michele Papa

Int. J. Mol. Sci. 2020, 21(4), 1539; https://doi.org/10.3390/ijms21041539 - 24 Feb 2020

Cited by 65 | Viewed by 8703

Abstract

The synaptic cleft has been vastly investigated in the last decades, leading to a novel and fascinating model of the functional and structural modifications linked to synaptic transmission and brain processing. The classic neurocentric model encompassing the neuronal pre- and post-synaptic terminals partly [...] Read more.

The synaptic cleft has been vastly investigated in the last decades, leading to a novel and fascinating model of the functional and structural modifications linked to synaptic transmission and brain processing. The classic neurocentric model encompassing the neuronal pre- and post-synaptic terminals partly explains the fine-tuned plastic modifications under both pathological and physiological circumstances. Recent experimental evidence has incontrovertibly added oligodendrocytes, astrocytes, and microglia as pivotal elements for synapse formation and remodeling (tripartite synapse) in both the developing and adult brain. Moreover, synaptic plasticity and its pathological counterpart (maladaptive plasticity) have shown a deep connection with other molecular elements of the extracellular matrix (ECM), once considered as a mere extracellular structural scaffold altogether with the cellular glue (i.e., glia). The ECM adds another level of complexity to the modern model of the synapse, particularly, for the long-term plasticity and circuit maintenance. This model, called tetrapartite synapse, can be further implemented by including the neurovascular unit (NVU) and the immune system. Although they were considered so far as tightly separated from the central nervous system (CNS) plasticity, at least in physiological conditions, recent evidence endorsed these elements as structural and paramount actors in synaptic plasticity. This scenario is, as far as speculations and evidence have shown, a consistent model for both adaptive and maladaptive plasticity. However, a comprehensive understanding of brain processes and circuitry complexity is still lacking. Here we propose that a better interpretation of the CNS complexity can be granted by a systems biology approach through the construction of predictive molecular models that enable to enlighten the regulatory logic of the complex molecular networks underlying brain function in health and disease, thus opening the way to more effective treatments. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity: Dynamic Changes in Neurons Functions)

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26 pages, 857 KiB

Open AccessReview

Synaptic GluN2A-Containing NMDA Receptors: From Physiology to Pathological Synaptic Plasticity

by Luca Franchini, Nicolò Carrano, Monica Di Luca and Fabrizio Gardoni

Int. J. Mol. Sci. 2020, 21(4), 1538; https://doi.org/10.3390/ijms21041538 - 24 Feb 2020

Cited by 79 | Viewed by 7876

Abstract

N-Methyl-d-Aspartate Receptors (NMDARs) are ionotropic glutamate-gated receptors. NMDARs are tetramers composed by several homologous subunits of GluN1-, GluN2-, or GluN3-type, leading to the existence in the central nervous system of a high variety of receptor subtypes with different pharmacological and signaling [...] Read more.

N-Methyl-d-Aspartate Receptors (NMDARs) are ionotropic glutamate-gated receptors. NMDARs are tetramers composed by several homologous subunits of GluN1-, GluN2-, or GluN3-type, leading to the existence in the central nervous system of a high variety of receptor subtypes with different pharmacological and signaling properties. NMDAR subunit composition is strictly regulated during development and by activity-dependent synaptic plasticity. Given the differences between GluN2 regulatory subunits of NMDAR in several functions, here we will focus on the synaptic pool of NMDARs containing the GluN2A subunit, addressing its role in both physiology and pathological synaptic plasticity as well as the contribution in these events of different types of GluN2A-interacting proteins. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity: Dynamic Changes in Neurons Functions)

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18 pages, 1406 KiB

Open AccessReview

Role of the Serotonin Receptor 7 in Brain Plasticity: From Development to Disease

by Marianna Crispino, Floriana Volpicelli and Carla Perrone-Capano

Int. J. Mol. Sci. 2020, 21(2), 505; https://doi.org/10.3390/ijms21020505 - 13 Jan 2020

Cited by 47 | Viewed by 9482

Abstract

Our knowledge on the plastic functions of the serotonin (5-HT) receptor subtype 7 (5-HT7R) in the brain physiology and pathology have advanced considerably in recent years. A wealth of data show that 5-HT7R is a key player in the establishment and remodeling of [...] Read more.

Our knowledge on the plastic functions of the serotonin (5-HT) receptor subtype 7 (5-HT7R) in the brain physiology and pathology have advanced considerably in recent years. A wealth of data show that 5-HT7R is a key player in the establishment and remodeling of neuronal cytoarchitecture during development and in the mature brain, and its dysfunction is linked to neuropsychiatric and neurodevelopmental diseases. The involvement of this receptor in synaptic plasticity is further demonstrated by data showing that its activation allows the rescue of long-term potentiation (LTP) and long-term depression (LTD) deficits in various animal models of neurodevelopmental diseases. In addition, it is becoming clear that the 5-HT7R is involved in inflammatory intestinal diseases, modulates the function of immune cells, and is likely to play a role in the gut-brain axis. In this review, we will mainly focus on recent findings on this receptor’s role in the structural and synaptic plasticity of the mammalian brain, although we will also illustrate novel aspects highlighted in gastrointestinal (GI) tract and immune system. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity: Dynamic Changes in Neurons Functions)

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23 pages, 2342 KiB

Open AccessReview

On the Modulatory Roles of Neuregulins/ErbB Signaling on Synaptic Plasticity

by Ada Ledonne and Nicola B. Mercuri

Int. J. Mol. Sci. 2020, 21(1), 275; https://doi.org/10.3390/ijms21010275 - 31 Dec 2019

Cited by 35 | Viewed by 7713

Abstract

Neuregulins (NRGs) are a family of epidermal growth factor-related proteins, acting on tyrosine kinase receptors of the ErbB family. NRGs play an essential role in the development of the nervous system, since they orchestrate vital functions such as cell differentiation, axonal growth, myelination, [...] Read more.

Neuregulins (NRGs) are a family of epidermal growth factor-related proteins, acting on tyrosine kinase receptors of the ErbB family. NRGs play an essential role in the development of the nervous system, since they orchestrate vital functions such as cell differentiation, axonal growth, myelination, and synapse formation. They are also crucially involved in the functioning of adult brain, by directly modulating neuronal excitability, neurotransmission, and synaptic plasticity. Here, we provide a review of the literature documenting the roles of NRGs/ErbB signaling in the modulation of synaptic plasticity, focusing on evidence reported in the hippocampus and midbrain dopamine (DA) nuclei. The emerging picture shows multifaceted roles of NRGs/ErbB receptors, which critically modulate different forms of synaptic plasticity (LTP, LTD, and depotentiation) affecting glutamatergic, GABAergic, and DAergic synapses, by various mechanisms. Further, we discuss the relevance of NRGs/ErbB-dependent synaptic plasticity in the control of brain processes, like learning and memory and the known involvement of NRGs/ErbB signaling in the modulation of synaptic plasticity in brain’s pathological conditions. Current evidence points to a central role of NRGs/ErbB receptors in controlling glutamatergic LTP/LTD and GABAergic LTD at hippocampal CA3–CA1 synapses, as well as glutamatergic LTD in midbrain DA neurons, thus supporting that NRGs/ErbB signaling is essential for proper brain functions, cognitive processes, and complex behaviors. This suggests that dysregulated NRGs/ErbB-dependent synaptic plasticity might contribute to mechanisms underlying different neurological and psychiatric disorders. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity: Dynamic Changes in Neurons Functions)

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13 pages, 1852 KiB

Open AccessReview

Modeling Resilience to Damage in Multiple Sclerosis: Plasticity Meets Connectivity

by Mario Stampanoni Bassi, Ennio Iezzi, Luigi Pavone, Georgia Mandolesi, Alessandra Musella, Antonietta Gentile, Luana Gilio, Diego Centonze and Fabio Buttari

Int. J. Mol. Sci. 2020, 21(1), 143; https://doi.org/10.3390/ijms21010143 - 24 Dec 2019

Cited by 10 | Viewed by 4564

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelinating white matter lesions and neurodegeneration, with a variable clinical course. Brain network architecture provides efficient information processing and resilience to damage. The peculiar organization characterized by [...] Read more.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelinating white matter lesions and neurodegeneration, with a variable clinical course. Brain network architecture provides efficient information processing and resilience to damage. The peculiar organization characterized by a low number of highly connected nodes (hubs) confers high resistance to random damage. Anti-homeostatic synaptic plasticity, in particular long-term potentiation (LTP), represents one of the main physiological mechanisms underlying clinical recovery after brain damage. Different types of synaptic plasticity, including both anti-homeostatic and homeostatic mechanisms (synaptic scaling), contribute to shape brain networks. In MS, altered synaptic functioning induced by inflammatory mediators may represent a further cause of brain network collapse in addition to demyelination and grey matter atrophy. We propose that impaired LTP expression and pathologically enhanced upscaling may contribute to disrupting brain network topology in MS, weakening resilience to damage and negatively influencing the disease course. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity: Dynamic Changes in Neurons Functions)

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17 pages, 944 KiB

Open AccessReview

Synaptic Plasticity Shapes Brain Connectivity: Implications for Network Topology

by Mario Stampanoni Bassi, Ennio Iezzi, Luana Gilio, Diego Centonze and Fabio Buttari

Int. J. Mol. Sci. 2019, 20(24), 6193; https://doi.org/10.3390/ijms20246193 - 8 Dec 2019

Cited by 83 | Viewed by 11831

Abstract

Studies of brain network connectivity improved understanding on brain changes and adaptation in response to different pathologies. Synaptic plasticity, the ability of neurons to modify their connections, is involved in brain network remodeling following different types of brain damage (e.g., vascular, neurodegenerative, inflammatory). [...] Read more.

Studies of brain network connectivity improved understanding on brain changes and adaptation in response to different pathologies. Synaptic plasticity, the ability of neurons to modify their connections, is involved in brain network remodeling following different types of brain damage (e.g., vascular, neurodegenerative, inflammatory). Although synaptic plasticity mechanisms have been extensively elucidated, how neural plasticity can shape network organization is far from being completely understood. Similarities existing between synaptic plasticity and principles governing brain network organization could be helpful to define brain network properties and reorganization profiles after damage. In this review, we discuss how different forms of synaptic plasticity, including homeostatic and anti-homeostatic mechanisms, could be directly involved in generating specific brain network characteristics. We propose that long-term potentiation could represent the neurophysiological basis for the formation of highly connected nodes (hubs). Conversely, homeostatic plasticity may contribute to stabilize network activity preventing poor and excessive connectivity in the peripheral nodes. In addition, synaptic plasticity dysfunction may drive brain network disruption in neuropsychiatric conditions such as Alzheimer’s disease and schizophrenia. Optimal network architecture, characterized by efficient information processing and resilience, and reorganization after damage strictly depend on the balance between these forms of plasticity. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity: Dynamic Changes in Neurons Functions)

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28 pages, 1401 KiB

Open AccessReview

Cell Clearing Systems Bridging Neuro-Immunity and Synaptic Plasticity

by Fiona Limanaqi, Francesca Biagioni, Carla Letizia Busceti, Larisa Ryskalin, Paola Soldani, Alessandro Frati and Francesco Fornai

Int. J. Mol. Sci. 2019, 20(9), 2197; https://doi.org/10.3390/ijms20092197 - 4 May 2019

Cited by 25 | Viewed by 5605

Abstract

In recent years, functional interconnections emerged between synaptic transmission, inflammatory/immune mediators, and central nervous system (CNS) (patho)-physiology. Such interconnections rose up to a level that involves synaptic plasticity, both concerning its molecular mechanisms and the clinical outcomes related to its behavioral abnormalities. Within [...] Read more.

In recent years, functional interconnections emerged between synaptic transmission, inflammatory/immune mediators, and central nervous system (CNS) (patho)-physiology. Such interconnections rose up to a level that involves synaptic plasticity, both concerning its molecular mechanisms and the clinical outcomes related to its behavioral abnormalities. Within this context, synaptic plasticity, apart from being modulated by classic CNS molecules, is strongly affected by the immune system, and vice versa. This is not surprising, given the common molecular pathways that operate at the cross-road between the CNS and immune system. When searching for a common pathway bridging neuro-immune and synaptic dysregulations, the two major cell-clearing cell clearing systems, namely the ubiquitin proteasome system (UPS) and autophagy, take center stage. In fact, just like is happening for the turnover of key proteins involved in neurotransmitter release, antigen processing within both peripheral and CNS-resident antigen presenting cells is carried out by UPS and autophagy. Recent evidence unravelling the functional cross-talk between the cell-clearing pathways challenged the traditional concept of autophagy and UPS as independent systems. In fact, autophagy and UPS are simultaneously affected in a variety of CNS disorders where synaptic and inflammatory/immune alterations concur. In this review, we discuss the role of autophagy and UPS in bridging synaptic plasticity with neuro-immunity, while posing a special emphasis on their interactions, which may be key to defining the role of immunity in synaptic plasticity in health and disease. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Synaptic Plasticity: Dynamic Changes in Neurons Functions)

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