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Dimensions of Synaptic Diseases: From Neurobiology to Therapy

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A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Molecular and Cellular Neuroscience".

Deadline for manuscript submissions: closed (16 February 2022) | Viewed by 10746

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Special Issue Editors

Dr. Daniel J. Whitcomb

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Guest Editor

Bristol Medical School, Faculty of Healthy Sciences, University of Bristol, Bristol, UK
Interests: neurophysiology; synaptic plasticity; neurodegeneration; glutamate receptors; hippocam-pus; non-invasive neuromodulation

Dr. Phil Regan

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Co-Guest Editor

Department of Biology & Biochemistry, University of Bath, Bath, UK
Interests: neuroinflammation; microglia; synaptic function; neurodegeneration; tau

Special Issue Information

Dear Colleagues,

The synapse sits at the heart of neuronal communication in the brain. It is therefore not surprising that numerous neurodevelopmental and neurodegenerative diseases are thought to have synaptic origins.

This Special Issue of Brain Sciences aims to collate studies, reviews and commentaries covering cutting-edge developments in our understanding of synaptic diseases and emerging therapeutic targets. Authors are invited to submit research articles and reviews that develop our understanding of synaptic dysregulation in disease, and how this can be targeted with emerging medical approaches. Topics include (but are not limited to) the synaptic basis of neurodevelopmental and neurodegenerative diseases; synaptic markers in disease phenotyping; tools and approaches to target the synapse in disease mechanism discovery; novel compounds to target synaptic molecules implicated in disease; and innovative interventions that target synapse function. We therefore invite papers that consider fundamental mechanisms of synapse function that are implicated in disease, profiling of synaptic function in disease states, and novel therapeutic interventions that target the synapse.

Dr. Daniel Whitcomb
Guest Editor

Dr. Phil Regan
Co-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. Brain Sciences is an international peer-reviewed open access monthly 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 2200 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

synapse
neurodegeneration
neurodevelopment
therapeutics
technologies

Published Papers (3 papers)

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Research

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24 pages, 4422 KiB

Open AccessArticle

Synaptic Dysfunction by Mutations in GRIN2B: Influence of Triheteromeric NMDA Receptors on Gain-of-Function and Loss-of-Function Mutant Classification

by Marwa Elmasri, James S. Lotti, Wajeeha Aziz, Oliver G. Steele, Eirini Karachaliou, Kenji Sakimura, Kasper B. Hansen and Andrew C. Penn

Brain Sci. 2022, 12(6), 789; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci12060789 - 15 Jun 2022

Cited by 7 | Viewed by 3683

Abstract

GRIN2B mutations are rare but often associated with patients having severe neurodevelopmental disorders with varying range of symptoms such as intellectual disability, developmental delay and epilepsy. Patient symptoms likely arise from mutations disturbing the role that the encoded NMDA receptor subunit, GluN2B, plays at neuronal connections in the developing nervous system. In this study, we investigated the cell-autonomous effects of putative gain- (GoF) and loss-of-function (LoF) missense GRIN2B mutations on excitatory synapses onto CA1 pyramidal neurons in organotypic hippocampal slices. In the absence of both native GluN2A and GluN2B subunits, functional incorporation into synaptic NMDA receptors was attenuated for GoF mutants, or almost eliminated for LoF GluN2B mutants. NMDA-receptor-mediated excitatory postsynaptic currents (NMDA-EPSCs) from synaptic GoF GluN1/2B receptors had prolonged decays consistent with their functional classification. Nonetheless, in the presence of native GluN2A, molecular replacement of native GluN2B with GoF and LoF GluN2B mutants all led to similar functional incorporation into synaptic receptors, more rapidly decaying NMDA-EPSCs and greater inhibition by TCN-201, a selective antagonist for GluN2A-containing NMDA receptors. Mechanistic insight was gained from experiments in HEK293T cells, which revealed that GluN2B GoF mutants slowed deactivation in diheteromeric GluN1/2B, but not triheteromeric GluN1/2A/2B receptors. We also show that a disease-associated missense mutation, which severely affects surface expression, causes opposing effects on NMDA-EPSC decay and charge transfer when introduced into GluN2A or GluN2B. Finally, we show that having a single null Grin2b allele has only a modest effect on NMDA-EPSC decay kinetics. Our results demonstrate that functional incorporation of GoF and LoF GluN2B mutants into synaptic receptors and the effects on EPSC decay times are highly dependent on the presence of triheteromeric GluN1/2A/2B NMDA receptors, thereby influencing the functional classification of NMDA receptor variants as GoF or LoF mutations. These findings highlight the complexity of interpreting effects of disease-causing NMDA receptor missense mutations in the context of neuronal function. Full article

(This article belongs to the Special Issue Dimensions of Synaptic Diseases: From Neurobiology to Therapy)

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13 pages, 39917 KiB

Open AccessArticle

Synapsin II Directly Suppresses Epileptic Seizures In Vivo

by Ryan Schwark, Rodrigo Andrade and Maria Bykhovskaia

Brain Sci. 2022, 12(3), 325; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci12030325 - 28 Feb 2022

Cited by 1 | Viewed by 2276

Abstract

The synapsin family offers a strong linkage between synaptic mechanisms and the epileptic phenotype. Synapsins are phosphoproteins reversibly associated with synaptic vesicles. Synapsin deficiency can cause epilepsy in humans, and synapsin II (SynII) in knockout (KO) mice causes generalized epileptic seizures. To differentiate between the direct effect of SynII versus its secondary adaptations, we used neonatal intracerebroventricular injections of the adeno-associated virus (AAV) expressing SynII. We found that SynII reintroduction diminished the enhanced synaptic activity in Syn2 KO hippocampal slices. Next, we employed the epileptogenic agent 4-aminopyridine (4-AP) and found that SynII reintroduction completely rescued the epileptiform activity observed in Syn2 KO slices upon 4-AP application. Finally, we developed a protocol to provoke behavioral seizures in young Syn2 KO animals and found that SynII reintroduction balances the behavioral seizures. To elucidate the mechanisms through which SynII suppresses hyperexcitability, we injected the phospho-incompetent version of Syn2 that had the mutated protein kinase A (PKA) phosphorylation site. The introduction of the phospho-incompetent SynII mutant suppressed the epileptiform and seizure activity in Syn2 KO mice, but not to the extent observed upon the reintroduction of native SynII. These findings show that SynII can directly suppress seizure activity and that PKA phosphorylation contributes to this function. Full article

(This article belongs to the Special Issue Dimensions of Synaptic Diseases: From Neurobiology to Therapy)

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Review

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21 pages, 1024 KiB

Open AccessReview

Focused Ultrasound Stimulation as a Neuromodulatory Tool for Parkinson’s Disease: A Scoping Review

by Keng Siang Lee, Benjamin Clennell, Tom G. J. Steward, Andriana Gialeli, Oscar Cordero-Llana and Daniel J. Whitcomb

Brain Sci. 2022, 12(2), 289; https://0-doi-org.brum.beds.ac.uk/10.3390/brainsci12020289 - 19 Feb 2022

Cited by 8 | Viewed by 4200

Abstract

Non-invasive focused ultrasound stimulation (FUS) is a non-ionising neuromodulatory technique that employs acoustic energy to acutely and reversibly modulate brain activity of deep-brain structures. It is currently being investigated as a potential novel treatment for Parkinson’s disease (PD). This scoping review was carried out to map available evidence pertaining to the provision of FUS as a PD neuromodulatory tool. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews, a search was applied to Ovid MEDLINE, Embase, Web of Science and Cochrane Central Register of Controlled Trials on 13 January 2022, with no limits applied. In total, 11 studies were included: 8 were from China and 1 each from Belgium, South Korea and Taiwan. All 11 studies were preclinical (6 in vivo, 2 in vitro, 2 mix of in vivo and in vitro and 1 in silico). The preclinical evidence indicates that FUS is safe and has beneficial neuromodulatory effects on motor behaviour in PD. FUS appears to have a therapeutic role in influencing the disease processes of PD, and therefore holds great promise as an attractive and powerful neuromodulatory tool for PD. Though these initial studies are encouraging, further study to understand the underlying cellular and molecular mechanisms is required before FUS can be routinely used in PD. Full article

(This article belongs to the Special Issue Dimensions of Synaptic Diseases: From Neurobiology to Therapy)

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