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Synaptic Plasticity and Diseases

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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 (30 June 2022) | Viewed by 32972

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Dr. Hiroki Toyoda

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Guest Editor

Graduate School of Dentistry, Osaka University, Suita, Japan
Interests: synaptic transmission; synaptic plasticity; ion channel; electrophysiology; cortex; trigeminal system
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Synaptic plasticity is a basic process in the brain that allows humans and animals to adapt to changes in their environment and is considered the neural basis of learning and memory as well as brain disorders including Alzheimer's disease, Parkinson's disease, autism, schizophrenia, mental retardation, chronic pain and drug addiction. Long-term potentiation (LTP) and long-term depression (LTD) are the most intensively studied forms of activity-dependent synaptic plasticity. It is now clear that that LTP and LTD are involved in many physiological functions and are linked to various brain disorders. An understanding of the cellular and molecular mechanisms of synaptic plasticity could aid the development of effective treatments for brain disorders. This Special Issue will be of interest to basic and clinical researchers involved in studies that focus on synaptic plasticity and diseases.

Dr. Hiroki Toyoda
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.

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Keywords

Synaptic plasticity
Long-term potentiation
Long-term depression
Learning
Memory
Brain disorders

Published Papers (10 papers)

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Research

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16 pages, 2028 KiB

Open AccessArticle

Restraint Stress and Repeated Corticosterone Administration Differentially Affect Neuronal Excitability, Synaptic Transmission and 5-HT₇ Receptor Reactivity in the Dorsal Raphe Nucleus of Young Adult Male Rats

by Joanna Bąk, Bartosz Bobula and Grzegorz Hess

Int. J. Mol. Sci. 2022, 23(22), 14303; https://doi.org/10.3390/ijms232214303 - 18 Nov 2022

Cited by 1 | Viewed by 1174

Abstract

Exogenous corticosterone administration reduces GABAergic transmission and impairs its 5-HT₇ receptor-dependent modulation in the rat dorsal raphe nucleus (DRN), but it is largely unknown how neuronal functions of the DRN are affected by repeated physical and psychological stress. This study compared the effects of repeated restraint stress and corticosterone injections on DRN neuronal excitability, spontaneous synaptic transmission, and its 5-HT₇ receptor-dependent modulation. Male Wistar rats received corticosterone injections for 7 or 14 days or were restrained for 10 min twice daily for 3 days. Repeated restraint stress and repeated corticosterone administration evoked similar changes in performance in the forced swim test. They increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) recorded from DRN neurons. In contrast to the treatment with corticosterone, restraint stress-induced changes in sEPSC kinetics and decreased intrinsic excitability of DRN neurons did not modify inhibitory transmission. Repeated injections of the 5-HT₇ receptor antagonist SB 269970 ameliorated the effects of restraint on excitability and sEPSC frequency but did not restore the altered kinetics of sEPSCs. Thus, repeated restraint stress and repeated corticosterone administration differ in consequences for the intrinsic excitability of DRN projection neurons and their excitatory and inhibitory synaptic inputs. Effects of repeated restraint stress on DRN neurons can be partially abrogated by blocking the 5-HT₇ receptor. Full article

(This article belongs to the Special Issue Synaptic Plasticity and Diseases)

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19 pages, 2496 KiB

Open AccessArticle

Cell-Type Specific Inhibition Controls the High-Frequency Oscillations in the Medial Entorhinal Cortex

by Shalva Gurgenidze, Peter Bäuerle, Dietmar Schmitz, Imre Vida, Tengis Gloveli and Tamar Dugladze

Int. J. Mol. Sci. 2022, 23(22), 14087; https://doi.org/10.3390/ijms232214087 - 15 Nov 2022

Cited by 2 | Viewed by 1656

Abstract

The medial entorhinal cortex (mEC) plays a critical role for spatial navigation and memory. While many studies have investigated the principal neurons within the entorhinal cortex, much less is known about the inhibitory circuitries within this structure. Here, we describe for the first time in the mEC a subset of parvalbumin-positive (PV+) interneurons (INs)—stuttering cells (STUT)—with morphological, intrinsic electrophysiological, and synaptic properties distinct from fast-spiking PV+ INs. In contrast to the fast-spiking PV+ INs, the axon of the STUT INs also terminated in layer 3 and showed subthreshold membrane oscillations at gamma frequencies. Whereas the synaptic output of the STUT INs was only weakly reduced by a μ-opioid agonist, their inhibitory inputs were strongly suppressed. Given these properties, STUT are ideally suited to entrain gamma activity in the pyramidal cell population of the mEC. We propose that activation of the μ-opioid receptors decreases the GABA release from the PV+ INs onto the STUT, resulting in disinhibition of the STUT cell population and the consequent increase in network gamma power. We therefore suggest that the opioid system plays a critical role, mediated by STUT INs, in the neural signaling and oscillatory network activity within the mEC. Full article

(This article belongs to the Special Issue Synaptic Plasticity and Diseases)

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16 pages, 2407 KiB

Open AccessArticle

New Positive TRPC6 Modulator Penetrates Blood–Brain Barrier, Eliminates Synaptic Deficiency and Restores Memory Deficit in 5xFAD Mice

by Nikita Zernov, Alexander V. Veselovsky, Vladimir V. Poroikov, Daria Melentieva, Anastasia Bolshakova and Elena Popugaeva

Int. J. Mol. Sci. 2022, 23(21), 13552; https://doi.org/10.3390/ijms232113552 - 04 Nov 2022

Cited by 4 | Viewed by 2761

Abstract

Synapse loss in the brain of Alzheimer’s disease patients correlates with cognitive dysfunctions. Drugs that limit synaptic loss are promising pharmacological agents. The transient receptor potential cation channel, subfamily C, member 6 (TRPC6) regulates the formation of an excitatory synapse. Positive regulation of TRPC6 results in increased synapse formation and enhances learning and memory in animal models. The novel selective TRPC6 agonist, 3-(3-,4-Dihydro-6,7-dimethoxy-3,3-dimethyl-1-isoquinolinyl)-2H-1-benzopyran-2-one, has recently been identified. Here we present in silico, in vitro, ex vivo, pharmacokinetic and in vivo studies of this compound. We demonstrate that it binds to the extracellular agonist binding site of the human TRPC6, protects hippocampal mushroom spines from amyloid toxicity in vitro, efficiently recovers synaptic plasticity in 5xFAD brain slices, penetrates the blood–brain barrier and recovers cognitive deficits in 5xFAD mice. We suggest that C20 might be recognized as the novel TRPC6-selective drug suitable to treat synaptic deficiency in Alzheimer’s disease-affected hippocampal neurons. Full article

(This article belongs to the Special Issue Synaptic Plasticity and Diseases)

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15 pages, 2568 KiB

Open AccessArticle

Nicotine Exposure during Adolescence Leads to Changes of Synaptic Plasticity and Intrinsic Excitability of Mice Insular Pyramidal Cells at Later Life

by Hiroki Toyoda and Kohei Koga

Int. J. Mol. Sci. 2022, 23(1), 34; https://doi.org/10.3390/ijms23010034 - 21 Dec 2021

Viewed by 1856

Abstract

To find satisfactory treatment for nicotine addiction, synaptic and cellular mechanisms should be investigated comprehensively. Synaptic transmission, plasticity and intrinsic excitability in various brain regions are known to be altered by acute nicotine exposure. However, it has not been addressed whether and how nicotine exposure during adolescence alters these synaptic events and intrinsic excitability in the insular cortex in adulthood. To address this question, we performed whole-cell patch-clamp recordings to examine the effects of adolescent nicotine exposure on synaptic transmission, plasticity and intrinsic excitability in layer V pyramidal neurons (PNs) of the mice insular cortex five weeks after the treatment. We found that excitatory synaptic transmission and potentiation were enhanced in these neurons. Following adolescent nicotine exposure, insular layer V PNs displayed enhanced intrinsic excitability, which was reflected in changes in relationship between current strength and spike number, inter-spike interval, spike current threshold and refractory period. In addition, spike-timing precision evaluated by standard deviation of spike timing was decreased following nicotine exposure. Our data indicate that adolescent nicotine exposure enhances synaptic transmission, plasticity and intrinsic excitability in layer V PNs of the mice insular cortex at later life, which might contribute to severe nicotine dependence in adulthood. Full article

(This article belongs to the Special Issue Synaptic Plasticity and Diseases)

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28 pages, 13880 KiB

Open AccessArticle

Hippocampal and Reticulo-Thalamic Parvalbumin Interneurons and Synaptic Re-Organization during Sleep Disorders in the Rat Models of Parkinson’s Disease Neuropathology

by Ljiljana Radovanovic, Jelena Petrovic and Jasna Saponjic

Int. J. Mol. Sci. 2021, 22(16), 8922; https://doi.org/10.3390/ijms22168922 - 19 Aug 2021

Cited by 4 | Viewed by 2506

Abstract

We investigated the alterations of hippocampal and reticulo-thalamic (RT) GABAergic parvalbumin (PV) interneurons and their synaptic re-organizations underlying the prodromal local sleep disorders in the distinct rat models of Parkinson’s disease (PD). We demonstrated for the first time that REM sleep is a predisposing state for the high-voltage sleep spindles (HVS) induction in all experimental models of PD, particularly during hippocampal REM sleep in the hemiparkinsonian models. There were the opposite underlying alterations of the hippocampal and RT GABAergic PV+ interneurons along with the distinct MAP2 and PSD-95 expressions. Whereas the PD cholinopathy enhanced the number of PV+ interneurons and suppressed the MAP2/PSD-95 expression, the hemiparkinsonism with PD cholinopathy reduced the number of PV+ interneurons and enhanced the MAP2/PSD-95 expression in the hippocampus. Whereas the PD cholinopathy did not alter PV+ interneurons but partially enhanced MAP2 and suppressed PSD-95 expression remotely in the RT, the hemiparkinsonism with PD cholinopathy reduced the PV+ interneurons, enhanced MAP2, and did not change PSD-95 expression remotely in the RT. Our study demonstrates for the first time an important regulatory role of the hippocampal and RT GABAergic PV+ interneurons and the synaptic protein dynamic alterations in the distinct rat models of PD neuropathology. Full article

(This article belongs to the Special Issue Synaptic Plasticity and Diseases)

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Review

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30 pages, 1915 KiB

Open AccessReview

Synapse Dysfunctions in Multiple Sclerosis

by Karin Schwarz and Frank Schmitz

Int. J. Mol. Sci. 2023, 24(2), 1639; https://doi.org/10.3390/ijms24021639 - 13 Jan 2023

Cited by 6 | Viewed by 4463

Abstract

Multiple sclerosis (MS) is a chronic neuroinflammatory disease of the central nervous system (CNS) affecting nearly three million humans worldwide. In MS, cells of an auto-reactive immune system invade the brain and cause neuroinflammation. Neuroinflammation triggers a complex, multi-faceted harmful process not only in the white matter but also in the grey matter of the brain. In the grey matter, neuroinflammation causes synapse dysfunctions. Synapse dysfunctions in MS occur early and independent from white matter demyelination and are likely correlates of cognitive and mental symptoms in MS. Disturbed synapse/glia interactions and elevated neuroinflammatory signals play a central role. Glutamatergic excitotoxic synapse damage emerges as a major mechanism. We review synapse/glia communication under normal conditions and summarize how this communication becomes malfunctional during neuroinflammation in MS. We discuss mechanisms of how disturbed glia/synapse communication can lead to synapse dysfunctions, signaling dysbalance, and neurodegeneration in MS. Full article

(This article belongs to the Special Issue Synaptic Plasticity and Diseases)

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20 pages, 1119 KiB

Open AccessReview

Norepinephrine, beyond the Synapse: Coordinating Epigenetic Codes for Memory

by Sabyasachi Maity, Raman Abbaspour, David Nahabedian and Steven A. Connor

Int. J. Mol. Sci. 2022, 23(17), 9916; https://doi.org/10.3390/ijms23179916 - 31 Aug 2022

Cited by 4 | Viewed by 2200

Abstract

The noradrenergic system is implicated in neuropathologies contributing to major disorders of the memory, including post-traumatic stress disorder and Alzheimer’s disease. Determining the impact of norepinephrine on cellular function and plasticity is thus essential for making inroads into our understanding of these brain conditions, while expanding our capacity for treating them. Norepinephrine is a neuromodulator within the mammalian central nervous system which plays important roles in cognition and associated synaptic plasticity. Specifically, norepinephrine regulates the formation of memory through the stimulation of β-ARs, increasing the dynamic range of synaptic modifiability. The mechanisms through which NE influences neural circuit function have been extended to the level of the epigenome. This review focuses on recent insights into how the noradrenergic recruitment of epigenetic modifications, including DNA methylation and post-translational modification of histones, contribute to homo- and heterosynaptic plasticity. These advances will be placed in the context of synaptic changes associated with memory formation and linked to brain disorders and neurotherapeutic applications. Full article

(This article belongs to the Special Issue Synaptic Plasticity and Diseases)

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22 pages, 1310 KiB

Open AccessReview

Actions of Metformin in the Brain: A New Perspective of Metformin Treatments in Related Neurological Disorders

by Nuojin Li, Tian Zhou and Erkang Fei

Int. J. Mol. Sci. 2022, 23(15), 8281; https://doi.org/10.3390/ijms23158281 - 27 Jul 2022

Cited by 13 | Viewed by 5810

Abstract

Metformin is a first-line drug for treating type 2 diabetes mellitus (T2DM) and one of the most commonly prescribed drugs in the world. Besides its hypoglycemic effects, metformin also can improve cognitive or mood functions in some T2DM patients; moreover, it has been reported that metformin exerts beneficial effects on many neurological disorders, including major depressive disorder (MDD), Alzheimer’s disease (AD) and Fragile X syndrome (FXS); however, the mechanism underlying metformin in the brain is not fully understood. Neurotransmission between neurons is fundamental for brain functions, and its defects have been implicated in many neurological disorders. Recent studies suggest that metformin appears not only to regulate synaptic transmission or plasticity in pathological conditions but also to regulate the balance of excitation and inhibition (E/I balance) in neural networks. In this review, we focused on and reviewed the roles of metformin in brain functions and related neurological disorders, which would give us a deeper understanding of the actions of metformin in the brain. Full article

(This article belongs to the Special Issue Synaptic Plasticity and Diseases)

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19 pages, 877 KiB

Open AccessReview

More than Addiction—The Nucleus Accumbens Contribution to Development of Mental Disorders and Neurodegenerative Diseases

by Martyna Bayassi-Jakowicka, Grazyna Lietzau, Ewelina Czuba, Cesare Patrone and Przemysław Kowiański

Int. J. Mol. Sci. 2022, 23(5), 2618; https://doi.org/10.3390/ijms23052618 - 27 Feb 2022

Cited by 16 | Viewed by 4050

Abstract

Stress and negative emotions evoked by social relationships and working conditions, frequently accompanied by the consumption of addictive substances, and metabolic and/or genetic predispositions, negatively affect brain function. One of the affected structures is nucleus accumbens (NAc). Although its function is commonly known to be associated with brain reward responses and addiction, a growing body of evidence also suggests its role in some mental disorders, such as depression and schizophrenia, as well as neurodegenerative diseases, such as Alzheimer’s, Huntington’s, and Parkinson’s. This may result from disintegration of the extensive connections based on numerous neurotransmitter systems, as well as impairment of some neuroplasticity mechanisms in the NAc. The consequences of NAc lesions are both morphological and functional. They include changes in the NAc’s volume, cell number, modifications of the neuronal dendritic tree and dendritic spines, and changes in the number of synapses. Alterations in the synaptic plasticity affect the efficiency of synaptic transmission. Modification of the number and structure of the receptors affects signaling pathways, the content of neuromodulators (e.g., BDNF) and transcription factors (e.g., pCREB, DeltaFosB, NFκB), and gene expression. Interestingly, changes in the NAc often have a different character and intensity compared to the changes observed in the other parts of the basal ganglia, in particular the dorsal striatum. In this review, we highlight the role of the NAc in various pathological processes in the context of its structural and functional damage, impaired connections with the other brain areas cooperating within functional systems, and progression of the pathological processes. Full article

(This article belongs to the Special Issue Synaptic Plasticity and Diseases)

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37 pages, 2878 KiB

Open AccessReview

Neuroplasticity and Multilevel System of Connections Determine the Integrative Role of Nucleus Accumbens in the Brain Reward System

by Martyna Bayassi-Jakowicka, Grazyna Lietzau, Ewelina Czuba, Aleksandra Steliga, Monika Waśkow and Przemysław Kowiański

Int. J. Mol. Sci. 2021, 22(18), 9806; https://doi.org/10.3390/ijms22189806 - 10 Sep 2021

Cited by 15 | Viewed by 5270

Abstract

A growing body of evidence suggests that nucleus accumbens (NAc) plays a significant role not only in the physiological processes associated with reward and satisfaction but also in many diseases of the central nervous system. Summary of the current state of knowledge on the morphological and functional basis of such a diverse function of this structure may be a good starting point for further basic and clinical research. The NAc is a part of the brain reward system (BRS) characterized by multilevel organization, extensive connections, and several neurotransmitter systems. The unique role of NAc in the BRS is a result of: (1) hierarchical connections with the other brain areas, (2) a well-developed morphological and functional plasticity regulating short- and long-term synaptic potentiation and signalling pathways, (3) cooperation among several neurotransmitter systems, and (4) a supportive role of neuroglia involved in both physiological and pathological processes. Understanding the complex function of NAc is possible by combining the results of morphological studies with molecular, genetic, and behavioral data. In this review, we present the current views on the NAc function in physiological conditions, emphasizing the role of its connections, neuroplasticity processes, and neurotransmitter systems. Full article

(This article belongs to the Special Issue Synaptic Plasticity and Diseases)

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