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Modulation of Neuronal Excitability, Synaptic Transmission, and Plasticity in Health and Disease

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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 December 2020) | Viewed by 35448

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Special Issue Editor

Prof. Dr. Claudio Grassi

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Guest Editor

Department of Neuroscience, Medical School, Università Cattolica del Sacro Cuore, Rome, Italy
Interests: molecular and cellular neuroscience; synaptic transmission and plasticity; neuronal excitability; neural stem cells and adult neurogenesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Brain functions rely on information encoding and its transmission within neural networks. As such, ion channels allowing the generation of electrical signals and governing neuronal excitability play a critical role in all physiological processes of central and peripheral nervous systems. Neuronal signaling also requires synaptic function to transmit information and allow elaboration of more complex responses in neural circuitries of the human brain. Of note, synaptic plasticity, i.e., changes in the synaptic strength, is pivotal for high-order processes such as learning and memory. Dysregulation of these physiological mechanisms controlling information encoding and its transmission, relying on ion channels, neurotransmitter receptors, and intracellular pathways regulating their expression and/or function, causes pathophysiological processes underlying major neuropsychiatric disorders. Therefore, the understanding of molecular and cellular mechanisms controlling neuronal excitability and synaptic function is fundamental for the insight into brain function and dysfunction. The scope of the Special Issue is to summarize and enhance knowledge in this field.

Authors are invited to submit original research, communications, and review articles which address the progress and current standing of neuronal excitability and synaptic function.

Topics include but are not limited to:

Ion channel function and their modulation;
Channelopathies;
Mechanisms governing neurotransmitter release;
Neurotransmitter receptors and transporters;
Altered synaptic function in neurological diseases;
Mechanistic links between candidate genes and brain disorders characterized by altered neuronal excitability and/or synaptic function.

Prof. Dr. Claudio Grassi
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

neuronal excitability
synaptic transmission
synaptic plasticity
neurotransmitter release
ion channels
neuron–glia interaction
neurodegenerative diseases

Published Papers (10 papers)

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Research

Jump to: Review

25 pages, 4348 KiB

Open AccessArticle

High-Fat Diet Leads to Reduced Protein O-GlcNAcylation and Mitochondrial Defects Promoting the Development of Alzheimer’s Disease Signatures

by Ilaria Zuliani, Chiara Lanzillotta, Antonella Tramutola, Eugenio Barone, Marzia Perluigi, Serena Rinaldo, Alessio Paone, Francesca Cutruzzolà, Francesco Bellanti, Matteo Spinelli, Francesca Natale, Salvatore Fusco, Claudio Grassi and Fabio Di Domenico

Int. J. Mol. Sci. 2021, 22(7), 3746; https://doi.org/10.3390/ijms22073746 - 3 Apr 2021

Cited by 18 | Viewed by 4053

Abstract

The disturbance of protein O-GlcNAcylation is emerging as a possible link between altered brain metabolism and the progression of neurodegeneration. As observed in brains with Alzheimer’s disease (AD), flaws of the cerebral glucose uptake translate into reduced protein O-GlcNAcylation, which promote the formation of pathological hallmarks. A high-fat diet (HFD) is known to foster metabolic dysregulation and insulin resistance in the brain and such effects have been associated with the reduction of cognitive performances. Remarkably, a significant role in HFD-related cognitive decline might be played by aberrant protein O-GlcNAcylation by triggering the development of AD signature and mitochondrial impairment. Our data support the impairment of total protein O-GlcNAcylation profile both in the brain of mice subjected to a 6-week high-fat-diet (HFD) and in our in vitro transposition on SH-SY5Y cells. The reduction of protein O-GlcNAcylation was associated with the development of insulin resistance, induced by overfeeding (i.e., defective insulin signaling and reduced mitochondrial activity), which promoted the dysregulation of the hexosamine biosynthetic pathway (HBP) flux, through the AMPK-driven reduction of GFAT1 activation. Further, we observed that a HFD induced the selective impairment of O-GlcNAcylated-tau and of O-GlcNAcylated-Complex I subunit NDUFB8, thus resulting in tau toxicity and reduced respiratory chain functionality respectively, highlighting the involvement of this posttranslational modification in the neurodegenerative process. Full article

(This article belongs to the Special Issue Modulation of Neuronal Excitability, Synaptic Transmission, and Plasticity in Health and Disease)

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Figure 1

12 pages, 1620 KiB

Open AccessCommunication

DNA Methyltransferase 1 (DNMT1) Shapes Neuronal Activity of Human iPSC-Derived Glutamatergic Cortical Neurons

by Sarah Bachmann, Jenice Linde, Michael Bell, Marc Spehr, Hans Zempel and Geraldine Zimmer-Bensch

Int. J. Mol. Sci. 2021, 22(4), 2034; https://doi.org/10.3390/ijms22042034 - 18 Feb 2021

Cited by 11 | Viewed by 4128

Abstract

Epigenetic mechanisms are emerging key players for the regulation of brain function, synaptic activity, and the formation of neuronal engrams in health and disease. As one important epigenetic mechanism of transcriptional control, DNA methylation was reported to distinctively modulate synaptic activity in excitatory and inhibitory cortical neurons in mice. Since DNA methylation signatures are responsive to neuronal activity, DNA methylation seems to contribute to the neuron’s capacity to adapt to and integrate changing activity patterns, being crucial for the plasticity and functionality of neuronal circuits. Since most studies addressing the role of DNA methylation in the regulation of synaptic function were conducted in mice or murine neurons, we here asked whether this functional implication applies to human neurons as well. To this end, we performed calcium imaging in human induced pluripotent stem cell (iPSC)-derived excitatory cortical neurons forming synaptic contacts and neuronal networks in vitro. Treatment with DNMT1 siRNA that diminishs the expression of the DNA (cytosine-5)-methyltransferase 1 (DNMT1) was conducted to investigate the functional relevance of DNMT1 as one of the main enzymes executing DNA methylations in the context of neuronal activity modulation. We observed a lowered proportion of actively firing neurons upon DNMT1-knockdown in these iPSC-derived excitatory neurons, pointing to a correlation of DNMT1-activity and synaptic transmission. Thus, our experiments suggest that DNMT1 decreases synaptic activity of human glutamatergic neurons and underline the relevance of epigenetic regulation of synaptic function also in human excitatory neurons. Full article

(This article belongs to the Special Issue Modulation of Neuronal Excitability, Synaptic Transmission, and Plasticity in Health and Disease)

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15 pages, 2575 KiB

Open AccessArticle

Single Administration of the T-Type Calcium Channel Enhancer SAK3 Reduces Oxidative Stress and Improves Cognition in Olfactory Bulbectomized Mice

by Dian Yuan, An Cheng, Ichiro Kawahata, Hisanao Izumi, Jing Xu and Kohji Fukunaga

Int. J. Mol. Sci. 2021, 22(2), 741; https://doi.org/10.3390/ijms22020741 - 13 Jan 2021

Cited by 3 | Viewed by 2491

Abstract

Alzheimer’s disease (AD), characterized by cognitive impairments, is considered to be one of the most widespread chronic neurodegenerative diseases worldwide. We recently introduced a novel therapeutic agent for AD treatment, the T-type calcium channel enhancer ethyl-8-methyl-2,4-dioxo-2-(piperidin-1-yl)-2H-spiro[cyclopentane-1,3-imidazo[1,2-a]pyridin]-2-ene-3-carboxylate (SAK3). SAK3 enhances calcium/calmodulin-dependent protein kinase II and proteasome activity, thereby promoting amyloid beta degradation in mice with AD. However, the antioxidative effects of SAK3 remain unclear. We investigated the antioxidative effects of SAK3 in olfactory bulbectomized mice (OBX mice), compared with the effects of donepezil as a positive control. As previously reported, single oral administration of both SAK3 (0.5 mg/kg, p.o.) and donepezil (1.0 mg/kg, p.o.) significantly improved cognitive and depressive behaviors in OBX mice. Single oral SAK3 administration markedly reduced 4-hydroxy-2-nonenal and nitrotyrosine protein levels in the hippocampus of OBX mice, which persisted until 1 week after administration. These effects are similar to those observed with donepezil therapy. Increased protein levels of oxidative stress markers were observed in the microglial cells, which were significantly rescued by SAK3 and donepezil. SAK3 could ameliorate oxidative stress in OBX mice, like donepezil, suggesting that the antioxidative effects of SAK3 and donepezil are among the neuroprotective mechanisms in AD pathogenesis. Full article

(This article belongs to the Special Issue Modulation of Neuronal Excitability, Synaptic Transmission, and Plasticity in Health and Disease)

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18 pages, 7724 KiB

Open AccessArticle

Crucial Role of FABP3 in αSyn-Induced Reduction of Septal GABAergic Neurons and Cognitive Decline in Mice

by Kazuya Matsuo, Yasushi Yabuki, Ronald Melki, Luc Bousset, Yuji Owada and Kohji Fukunaga

Int. J. Mol. Sci. 2021, 22(1), 400; https://doi.org/10.3390/ijms22010400 - 1 Jan 2021

Cited by 2 | Viewed by 2923

Abstract

In synucleinopathies, while motor symptoms are thought to be attributed to the accumulation of misfolded α-synuclein (αSyn) in nigral dopaminergic neurons, it remains to be elucidated how cognitive decline arises. Here, we investigated the effects of distinct αSyn strains on cognition and the related neuropathology in the medial septum/diagonal band (MS/DB), a key region for cognitive processing. Bilateral injection of αSyn fibrils into the dorsal striatum potently impaired cognition in mice. The cognitive decline was accompanied by accumulation of phosphorylated αSyn at Ser129 and reduction of gamma-aminobutyric acid (GABA)-ergic but not cholinergic neurons in the MS/DB. Since we have demonstrated that fatty acid-binding protein 3 (FABP3) is critical for αSyn neurotoxicity in nigral dopaminergic neurons, we investigated whether FABP3 also participates in αSyn pathology in the MS/DB and cognitive decline. FABP3 was highly expressed in GABAergic but rarely in cholinergic neurons in the MS/DB. Notably, Fabp3 deletion antagonized the accumulation of phosphorylated αSyn, decrease in GABAergic neurons, and cognitive impairment caused by αSyn fibrils. Overall, the present study indicates that FABP3 mediates αSyn neurotoxicity in septal GABAergic neurons and the resultant cognitive impairment, and that FABP3 in this subpopulation could be a therapeutic target for dementia in synucleinopathies. Full article

(This article belongs to the Special Issue Modulation of Neuronal Excitability, Synaptic Transmission, and Plasticity in Health and Disease)

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13 pages, 1920 KiB

Open AccessArticle

REDD1 Is Involved in Amyloid β-Induced Synaptic Dysfunction and Memory Impairment

by Jee Hyun Yi, Huiyoung Kwon, Eunbi Cho, Jieun Jeon, Jeongwon Lee, Young Choon Lee, Jong Hyun Cho, Mira Jun, Minho Moon, Jong Hoon Ryu, Ji-Su Kim, Ji Woong Choi, Se Jin Park, Seungheon Lee and Dong Hyun Kim

Int. J. Mol. Sci. 2020, 21(24), 9482; https://doi.org/10.3390/ijms21249482 - 13 Dec 2020

Cited by 6 | Viewed by 2608

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by neurological dysfunction, including memory impairment, attributed to the accumulation of amyloid β (Aβ) in the brain. Although several studies reported possible mechanisms involved in Aβ pathology, much remains unknown. Previous findings suggested that a protein regulated in development and DNA damage response 1 (REDD1), a stress-coping regulator, is an Aβ-responsive gene involved in Aβ cytotoxicity. However, we still do not know how Aβ increases the level of REDD1 and whether REDD1 mediates Aβ-induced synaptic dysfunction. To elucidate this, we examined the effect of Aβ on REDD1-expression using acute hippocampal slices from mice, and the effect of REDD1 short hairpin RNA (shRNA) on Aβ-induced synaptic dysfunction. Lastly, we observed the effect of REDD1 shRNA on memory deficit in an AD-like mouse model. Through the experiments, we found that Aβ-incubated acute hippocampal slices showed increased REDD1 levels. Moreover, Aβ injection into the lateral ventricle increased REDD1 levels in the hippocampus. Anisomycin, but not actinomycin D, blocked Aβ-induced increase in REDD1 levels in the acute hippocampal slices, suggesting that Aβ may increase REDD1 translation rather than transcription. Aβ activated Fyn/ERK/S6 cascade, and inhibitors for Fyn/ERK/S6 or mGluR5 blocked Aβ-induced REDD1 upregulation. REDD1 inducer, a transcriptional activator, and Aβ blocked synaptic plasticity in the acute hippocampal slices. REDD1 inducer inhibited mTOR/Akt signaling. REDD1 shRNA blocked Aβ-induced synaptic deficits. REDD1 shRNA also blocked Aβ-induced memory deficits in passive-avoidance and object-recognition tests. Collectively, these results demonstrate that REDD1 participates in Aβ pathology and could be a target for AD therapy. Full article

(This article belongs to the Special Issue Modulation of Neuronal Excitability, Synaptic Transmission, and Plasticity in Health and Disease)

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15 pages, 3498 KiB

Open AccessArticle

Neural Stem Cell-Derived Exosomes Revert HFD-Dependent Memory Impairment via CREB-BDNF Signalling

by Matteo Spinelli, Francesca Natale, Marco Rinaudo, Lucia Leone, Daniele Mezzogori, Salvatore Fusco and Claudio Grassi

Int. J. Mol. Sci. 2020, 21(23), 8994; https://doi.org/10.3390/ijms21238994 - 26 Nov 2020

Cited by 21 | Viewed by 3150

Abstract

Overnutrition and metabolic disorders impair cognitive functions through molecular mechanisms still poorly understood. In mice fed with a high fat diet (HFD) we analysed the expression of synaptic plasticity-related genes and the activation of cAMP response element-binding protein (CREB)-brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signalling. We found that a HFD inhibited both CREB phosphorylation and the expression of a set of CREB target genes in the hippocampus. The intranasal administration of neural stem cell (NSC)-derived exosomes (exo-NSC) epigenetically restored the transcription of Bdnf, nNOS, Sirt1, Egr3, and RelA genes by inducing the recruitment of CREB on their regulatory sequences. Finally, exo-NSC administration rescued both BDNF signalling and memory in HFD mice. Collectively, our findings highlight novel mechanisms underlying HFD-related memory impairment and provide evidence of the potential therapeutic effect of exo-NSC against metabolic disease-related cognitive decline. Full article

(This article belongs to the Special Issue Modulation of Neuronal Excitability, Synaptic Transmission, and Plasticity in Health and Disease)

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Review

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13 pages, 780 KiB

Open AccessReview

Emerging Roles of Protease-Activated Receptors (PARs) in the Modulation of Synaptic Transmission and Plasticity

by Rachel Price, Nicola Biagio Mercuri and Ada Ledonne

Int. J. Mol. Sci. 2021, 22(2), 869; https://doi.org/10.3390/ijms22020869 - 16 Jan 2021

Cited by 4 | Viewed by 3145

Abstract

Protease-activated receptors (PARs) are a class of G protein-coupled receptors (GPCRs) with a unique mechanism of activation, prompted by a proteolytic cleavage in their N-terminal domain that uncovers a tethered ligand, which binds and stimulates the same receptor. PARs subtypes (PAR1-4) have well-documented roles in coagulation, hemostasis, and inflammation, and have been deeply investigated for their function in cellular survival/degeneration, while their roles in the brain in physiological conditions remain less appreciated. Here, we describe PARs’ effects in the modulation of neurotransmission and synaptic plasticity. Available evidence, mainly concerning PAR1-mediated and PAR2-mediated regulation of glutamatergic and GABAergic transmission, supports that PARs are important modulators of synaptic efficacy and plasticity in normal conditions. Full article

(This article belongs to the Special Issue Modulation of Neuronal Excitability, Synaptic Transmission, and Plasticity in Health and Disease)

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19 pages, 2614 KiB

Open AccessReview

Neurotransmitter Release Site Replenishment and Presynaptic Plasticity

by Sumiko Mochida

Int. J. Mol. Sci. 2021, 22(1), 327; https://doi.org/10.3390/ijms22010327 - 30 Dec 2020

Cited by 13 | Viewed by 4514

Abstract

An action potential (AP) triggers neurotransmitter release from synaptic vesicles (SVs) docking to a specialized release site of presynaptic plasma membrane, the active zone (AZ). The AP simultaneously controls the release site replenishment with SV for sustainable synaptic transmission in response to incoming neuronal signals. Although many studies have suggested that the replenishment time is relatively slow, recent studies exploring high speed resolution have revealed SV dynamics with milliseconds timescale after an AP. Accurate regulation is conferred by proteins sensing Ca²⁺ entering through voltage-gated Ca²⁺ channels opened by an AP. This review summarizes how millisecond Ca²⁺ dynamics activate multiple protein cascades for control of the release site replenishment with release-ready SVs that underlie presynaptic short-term plasticity. Full article

(This article belongs to the Special Issue Modulation of Neuronal Excitability, Synaptic Transmission, and Plasticity in Health and Disease)

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25 pages, 2256 KiB

Open AccessReview

The Signaling Pathways Involved in the Anticonvulsive Effects of the Adenosine A₁ Receptor

by Jeroen Spanoghe, Lars E. Larsen, Erine Craey, Simona Manzella, Annelies Van Dycke, Paul Boon and Robrecht Raedt

Int. J. Mol. Sci. 2021, 22(1), 320; https://doi.org/10.3390/ijms22010320 - 30 Dec 2020

Cited by 6 | Viewed by 3867

Abstract

Adenosine acts as an endogenous anticonvulsant and seizure terminator in the brain. Many of its anticonvulsive effects are mediated through the activation of the adenosine A₁ receptor, a G protein-coupled receptor with a wide array of targets. Activating A₁ receptors is an effective approach to suppress seizures. This review gives an overview of the neuronal targets of the adenosine A₁ receptor focusing in particular on signaling pathways resulting in neuronal inhibition. These include direct interactions of G protein subunits, the adenyl cyclase pathway and the phospholipase C pathway, which all mediate neuronal hyperpolarization and suppression of synaptic transmission. Additionally, the contribution of the guanyl cyclase and mitogen-activated protein kinase cascades to the seizure-suppressing effects of A₁ receptor activation are discussed. This review ends with the cautionary note that chronic activation of the A₁ receptor might have detrimental effects, which will need to be avoided when pursuing A₁ receptor-based epilepsy therapies. Full article

(This article belongs to the Special Issue Modulation of Neuronal Excitability, Synaptic Transmission, and Plasticity in Health and Disease)

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26 pages, 1621 KiB

Open AccessReview

Candidate Strategies for Development of a Rapid-Acting Antidepressant Class That Does Not Result in Neuropsychiatric Adverse Effects: Prevention of Ketamine-Induced Neuropsychiatric Adverse Reactions

by Motohiro Okada, Yasuhiro Kawano, Kouji Fukuyama, Eishi Motomura and Takashi Shiroyama

Int. J. Mol. Sci. 2020, 21(21), 7951; https://doi.org/10.3390/ijms21217951 - 26 Oct 2020

Cited by 16 | Viewed by 3199

Abstract

Non-competitive N-methyl-D-aspartate/glutamate receptor (NMDAR) antagonism has been considered to play important roles in the pathophysiology of schizophrenia. In spite of severe neuropsychiatric adverse effects, esketamine (racemic enantiomer of ketamine) has been approved for the treatment of conventional monoaminergic antidepressant-resistant depression. Furthermore, ketamine improves anhedonia, suicidal ideation and bipolar depression, for which conventional monoaminergic antidepressants are not fully effective. Therefore, ketamine has been accepted, with rigorous restrictions, in psychiatry as a new class of antidepressant. Notably, the dosage of ketamine for antidepressive action is comparable to the dose that can generate schizophrenia-like psychotic symptoms. Furthermore, the psychotropic effects of ketamine precede the antidepressant effects. The maintenance of the antidepressive efficacy of ketamine often requires repeated administration; however, repeated ketamine intake leads to abuse and is consistently associated with long-lasting memory-associated deficits. According to the dissociative anaesthetic feature of ketamine, it exerts broad acute influences on cognition/perception. To evaluate the therapeutic validation of ketamine across clinical contexts, including its advantages and disadvantages, psychiatry should systematically assess the safety and efficacy of either short- and long-term ketamine treatments, in terms of both acute and chronic outcomes. Here, we describe the clinical evidence of NMDAR antagonists, and then the temporal mechanisms of schizophrenia-like and antidepressant-like effects of the NMDAR antagonist, ketamine. The underlying pharmacological rodent studies will also be discussed. Full article

(This article belongs to the Special Issue Modulation of Neuronal Excitability, Synaptic Transmission, and Plasticity in Health and Disease)

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