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Dysfunctional Neural Circuits and Impairments in Brain Function
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Dysfunctional Neural Circuits and Impairments in Brain Function

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 (20 February 2025) | Viewed by 7487

Special Issue Editors

Prof. Dr. Takashi Tominaga

E-Mail Website
Guest Editor
Institute of Neuroscience & Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Sanuki 769-2193, Kagawa, Japan
Interests: neural circuits; neuropsychiatric disorders; ASD; AD; schizophrenia; depression; and PTSD
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Ichiro Takashima

E-Mail Website
Guest Editor
Department of Informatics and Electronics, Daiichi Institute of Technology, Tokyo, Japan
Interests: neural circuits; in vivo optical recording; Parkinson’s desease; thalamic syndrome; dysesthesia; ischemic stroke; chronic pain

Special Issue Information

Dear Colleagues,

We would like to invite researchers to submit their original research articles, reviews, and perspectives to our upcoming special issue on "Dysfunctional Neural Circuits and Impairments in Brain Function". This issue will explore the latest advances in understanding the link between abnormal neural circuits and neuropsychiatric disorders, developmental impairments, and cognitive deficits. It is increasingly recognized that some neuropsychiatric disorders, especially developmental diseases like Autism Spectrum Disorder and Schizophrenia, as well as some types of dementia such as Alzheimer's disease, are caused by dysfunctions in neural circuit activity. Therefore, it is important to capture the dynamics of neural circuits at both the local and whole brain levels. The issue welcomes papers that also investigate the toxicological effects of drugs and environmental factors that can cause malfunction of brain activity. We welcome submissions covering a range of topics related to the subject, including the underlying mechanisms of neural circuit dysfunction, clinical implications for diagnosis and treatment, and technical approaches for capturing neural circuit dysfunction. In particular, we encourage authors to submit technical papers that deal with optical recording and other comprehensive methods for measuring neural circuit function. We encourage authors to submit their work early to ensure ample time for peer review and timely publication. We believe that this special issue will make a significant contribution to the field of neuroscience and lead to new approaches for diagnosing and treating a wide range of cognitive impairments.

Prof. Dr. Takashi Tominaga
Prof. Dr. Ichiro Takashima
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. 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

  • neural circuits
  • dysfunctional circuits
  • neuropsychiatric disorders
  • optical recording
  • voltage-sensitive dyes
  • genetically encoded optical indicators
  • local brain activity
  • whole brain activity
  • cognitive impairments
  • behavioral test

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Related Special Issue

Published Papers (6 papers)

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Research

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16 pages, 3412 KiB  
Article
Reparixin as a Potential Antiepileptogenic Agent: Modulation of the CXCL1–CXCR1/2 Axis and Seizure Activity in a Kindling Rat Model of Temporal Lobe Epilepsy
by Nihan Çarçak, Nursima Mutlu, Elif Tuğçe Erdeve, Talat Taygun Turan, Özge Sarıyıldız, Canan Ulusoy, Elif Şanlı, Erdem Tüzün, Cem İsmail Küçükali, Laura Brandolini, Andrea Aramini, Marcello Allegretti, Filiz Onat and Lidia De Filippis
Int. J. Mol. Sci. 2025, 26(7), 2831; https://doi.org/10.3390/ijms26072831 - 21 Mar 2025
Viewed by 481
Abstract
Chemokine (CXC motif) ligand 8 (CXCL8) is a pro-inflammatory chemokine binding to CXC motif receptors 1/2 (CXCR1/2). Patients with temporal lobe epilepsy (TLE) exhibit increased serum CXCL8 levels. CXC motif ligand 1 (CXCL1), a murine ortholog of CXCL8, has been implicated in seizure [...] Read more.
Chemokine (CXC motif) ligand 8 (CXCL8) is a pro-inflammatory chemokine binding to CXC motif receptors 1/2 (CXCR1/2). Patients with temporal lobe epilepsy (TLE) exhibit increased serum CXCL8 levels. CXC motif ligand 1 (CXCL1), a murine ortholog of CXCL8, has been implicated in seizure generation and neuronal loss. This study evaluated the antiepileptogenic and antiseizure effects of reparixin in amygdaloid kindling rat model of TLE. Reparixin was administered during the kindling period for 14 days, and seizures were induced twice daily via electrical stimulation. To assess the antiseizure effects, reparixin was administered to fully kindled animals, and stimulations were performed 24 and 48 h later. Levetiracetam, a broad-spectrum antiseizure drug, was administered intraperitoneally (i.p.) as positive control 1 h before each stimulation. Reparixin delayed secondary seizure generalization during kindling. Reparixin reduced seizure severity and after-discharge duration in fully kindled animals at 24 h from treatment initiation. CXCR1/2 and protein kinase B pathway proteins exhibited no significant changes; reparixin reduced the phospho-extracellular signal-regulated kinase (pERK)/ERK ratio in the cortex and hippocampus. CXCL1 expression was significantly decreased in the cortex. Reparixin exhibited antiepileptogenic and partial antiseizure effects by modulating the CXCL1–CXCR1/2 axis and reducing ERK signaling. Already in clinical trials on respiratory diseases, reparixin could be repurposed for epilepsy therapy. Full article
(This article belongs to the Special Issue Dysfunctional Neural Circuits and Impairments in Brain Function)
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14 pages, 2642 KiB  
Article
Engineering of Genetically Encoded Bright Near-Infrared Fluorescent Voltage Indicator
by Xian Xiao, Aimei Yang, Hanbin Zhang, Demian Park, Yangdong Wang, Balint Szabo, Edward S. Boyden and Kiryl D. Piatkevich
Int. J. Mol. Sci. 2025, 26(4), 1442; https://doi.org/10.3390/ijms26041442 - 8 Feb 2025
Viewed by 1532
Abstract
Genetically encoded voltage indicators (GEVIs) allow for the cell-type-specific real-time imaging of neuronal membrane potential dynamics, which is essential to understanding neuronal information processing at both cellular and circuit levels. Among GEVIs, near-infrared-shifted GEVIs offer faster kinetics, better tissue penetration, and compatibility with [...] Read more.
Genetically encoded voltage indicators (GEVIs) allow for the cell-type-specific real-time imaging of neuronal membrane potential dynamics, which is essential to understanding neuronal information processing at both cellular and circuit levels. Among GEVIs, near-infrared-shifted GEVIs offer faster kinetics, better tissue penetration, and compatibility with optogenetic tools, enabling all-optical electrophysiology in complex biological contexts. In our previous work, we employed the directed molecular evolution of microbial rhodopsin Archaerhodopsin-3 (Arch-3) in mammalian cells to develop a voltage sensor called Archon1. Archon1 demonstrated excellent membrane localization, signal-to-noise ratio (SNR), sensitivity, kinetics, and photostability, and full compatibility with optogenetic tools. However, Archon1 suffers from low brightness and requires high illumination intensities, which leads to tissue heating and phototoxicity during prolonged imaging. In this study, we aim to improve the brightness of this voltage sensor. We performed random mutation on a bright Archon derivative and identified a novel variant, monArch, which exhibits satisfactory voltage sensitivity (4~5% ΔF/FAP) and a 9-fold increase in basal brightness compared with Archon1. However, it is hindered by suboptimal membrane localization and compromised voltage sensitivity. These challenges underscore the need for continued optimization to achieve an optimal balance of brightness, stability, and functionality in rhodopsin-based voltage sensors. Full article
(This article belongs to the Special Issue Dysfunctional Neural Circuits and Impairments in Brain Function)
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15 pages, 8782 KiB  
Article
Impaired Hippocampal Long-Term Potentiation and Memory Deficits upon Haploinsufficiency of MDGA1 Can Be Rescued by Acute Administration of D-Cycloserine
by Daiki Ojima, Yoko Tominaga, Takashi Kubota, Atsushi Tada, Hiroo Takahashi, Yasushi Kishimoto, Takashi Tominaga and Tohru Yamamoto
Int. J. Mol. Sci. 2024, 25(17), 9674; https://doi.org/10.3390/ijms25179674 - 6 Sep 2024
Cited by 1 | Viewed by 1491
Abstract
The maintenance of proper brain function relies heavily on the balance of excitatory and inhibitory neural circuits, governed in part by synaptic adhesion molecules. Among these, MDGA1 (MAM domain-containing glycosylphosphatidylinositol anchor 1) acts as a suppressor of synapse formation by interfering with Neuroligin-mediated [...] Read more.
The maintenance of proper brain function relies heavily on the balance of excitatory and inhibitory neural circuits, governed in part by synaptic adhesion molecules. Among these, MDGA1 (MAM domain-containing glycosylphosphatidylinositol anchor 1) acts as a suppressor of synapse formation by interfering with Neuroligin-mediated interactions, crucial for maintaining the excitatory–inhibitory (E/I) balance. Mdga1−/− mice exhibit selectively enhanced inhibitory synapse formation in their hippocampal pyramidal neurons, leading to impaired hippocampal long-term potentiation (LTP) and hippocampus-dependent learning and memory function; however, it has not been fully investigated yet if the reduction in MDGA1 protein levels would alter brain function. Here, we examined the behavioral and synaptic consequences of reduced MDGA1 protein levels in Mdga1+/− mice. As observed in Mdga1−/− mice, Mdga1+/− mice exhibited significant deficits in hippocampus-dependent learning and memory tasks, such as the Morris water maze and contextual fear-conditioning tests, along with a significant deficit in the long-term potentiation (LTP) in hippocampal Schaffer collateral CA1 synapses. The acute administration of D-cycloserine, a co-agonist of NMDAR (N-methyl-d-aspartate receptor), significantly ameliorated memory impairments and restored LTP deficits specifically in Mdga1+/− mice, while having no such effect on Mdga1−/− mice. These results highlight the critical role of MDGA1 in regulating inhibitory synapse formation and maintaining the E/I balance for proper cognitive function. These findings may also suggest potential therapeutic strategies targeting the E/I imbalance to alleviate cognitive deficits associated with neuropsychiatric disorders. Full article
(This article belongs to the Special Issue Dysfunctional Neural Circuits and Impairments in Brain Function)
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17 pages, 3202 KiB  
Article
Neuroligin-3-Mediated Synapse Formation Strengthens Interactions between Hippocampus and Barrel Cortex in Associative Memory
by Huajuan Xiao, Yang Xu, Shan Cui and Jin-Hui Wang
Int. J. Mol. Sci. 2024, 25(2), 711; https://doi.org/10.3390/ijms25020711 - 5 Jan 2024
Viewed by 1439
Abstract
Memory traces are believed to be broadly allocated in cerebral cortices and the hippocampus. Mutual synapse innervations among these brain areas are presumably formed in associative memory. In the present study, we have used neuronal tracing by pAAV-carried fluorescent proteins and neuroligin-3 mRNA [...] Read more.
Memory traces are believed to be broadly allocated in cerebral cortices and the hippocampus. Mutual synapse innervations among these brain areas are presumably formed in associative memory. In the present study, we have used neuronal tracing by pAAV-carried fluorescent proteins and neuroligin-3 mRNA knockdown by shRNAs to examine the role of neuroligin-3-mediated synapse formation in the interconnection between primary associative memory cells in the sensory cortices and secondary associative memory cells in the hippocampus during the acquisition and memory of associated signals. Our studies show that mutual synapse innervations between the barrel cortex and the hippocampal CA3 region emerge and are upregulated after the memories of associated whisker and odor signals come into view. These synapse interconnections are downregulated by a knockdown of neuroligin-3-mediated synapse linkages. New synapse interconnections and the strengthening of these interconnections appear to endorse the belief in an interaction between the hippocampus and sensory cortices for memory consolidation. Full article
(This article belongs to the Special Issue Dysfunctional Neural Circuits and Impairments in Brain Function)
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Review

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34 pages, 1829 KiB  
Review
Deciphering the Functions of Raphe–Hippocampal Serotonergic and Glutamatergic Circuits and Their Deficits in Alzheimer’s Disease
by Wanting Yu, Ruonan Zhang, Aohan Zhang and Yufei Mei
Int. J. Mol. Sci. 2025, 26(3), 1234; https://doi.org/10.3390/ijms26031234 - 30 Jan 2025
Viewed by 1071
Abstract
Subcortical innervation of the hippocampus by the raphe nucleus is essential for emotional and cognitive control. The two major afferents from raphe to hippocampus originate from serotonergic and glutamatergic neurons, of which the serotonergic control of hippocampal inhibitory network, theta activity, and synaptic [...] Read more.
Subcortical innervation of the hippocampus by the raphe nucleus is essential for emotional and cognitive control. The two major afferents from raphe to hippocampus originate from serotonergic and glutamatergic neurons, of which the serotonergic control of hippocampal inhibitory network, theta activity, and synaptic plasticity have been extensively explored in the growing body of literature, whereas those of glutamatergic circuits have received little attention. Notably, both serotonergic and glutamatergic circuits between raphe and hippocampus are disrupted in Alzheimer’s disease (AD), which may contribute to initiation and progression of behavioral and psychological symptoms of dementia. Thus, deciphering the mechanism underlying abnormal raphe–hippocampal circuits in AD is crucial to prevent dementia-associated emotional and cognitive symptoms. In this review, we summarize the anatomical, neurochemical, and electrophysiological diversity of raphe nuclei as well as the architecture of raphe–hippocampal circuitry. We then elucidate subcortical control of hippocampal activity by raphe nuclei and their role in regulation of emotion and cognition. Additionally, we present an overview of disrupted raphe–hippocampal circuits in AD pathogenesis and analyze the available therapies that can potentially be used clinically to alleviate the neuropsychiatric symptoms and cognitive decline in AD course. Full article
(This article belongs to the Special Issue Dysfunctional Neural Circuits and Impairments in Brain Function)
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Other

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11 pages, 236 KiB  
Perspective
A New Perspective on Agitation in Alzheimer’s Disease: A Potential Paradigm Shift
by John R. Ostergaard
Int. J. Mol. Sci. 2025, 26(7), 3370; https://doi.org/10.3390/ijms26073370 - 4 Apr 2025
Viewed by 401
Abstract
Agitation is a common and difficult-to-manage neuropsychiatric syndrome in dementia. Recently, an association with the autonomous nervous system has been suggested. From the literature researched, however, only two studies investigating autonomic function concomitant to agitation situations appeared; one case series comprised two American [...] Read more.
Agitation is a common and difficult-to-manage neuropsychiatric syndrome in dementia. Recently, an association with the autonomous nervous system has been suggested. From the literature researched, however, only two studies investigating autonomic function concomitant to agitation situations appeared; one case series comprised two American veterans with vascular and Alzheimer’s dementia, respectively, and in a case series of patients with CLN3 (juvenile neuronal ceroid lipofuscinosis), this was found to be the most common neurodegenerative disease leading to dementia in childhood. In both case series, the measurement of the autonomic system disclosed a parasympathetic withdrawal and sympathetic hyperactivity in the temporal context with agitated behavior. If the time-wise-related autonomic imbalance shown previously can be demonstrated in a larger cohort of patients with Alzheimer’s disease, the use of transcutaneous vagal stimulation might be a potential paradigm shift in the treatment of agitation in Alzheimer’s disease. Full article
(This article belongs to the Special Issue Dysfunctional Neural Circuits and Impairments in Brain Function)
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