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25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology

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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: 31 December 2025 | Viewed by 12753

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Prof. Dr. Kiminobu Sugaya

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College of Medicine, University of Central Florida, Orlando, FL 32816, USA
Interests: stem cell; Alzheimer’s disease; neurodegenerative diseases; down syndrome; regeneration therapy; cancer stem cell; exosome
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Special Issue Information

Dear Colleagues,

The field of molecular neurobiology has undergone a remarkable transformation over the past 25 years, driven by rapid technological advances and deepening insights into the fundamental mechanisms governing brain development, function, and disease. In celebration of the 25th anniversary of the International Journal of Molecular Sciences (IJMS), this Special Issue, “25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology”, aims to highlight the latest developments, unresolved questions, and future directions in this dynamic and interdisciplinary area of research.

We welcome contributions that explore molecular and cellular processes underlying neural function and dysfunction. Topics of interest include but are not limited to the following: intracellular and intercellular signaling in neurons and glia, transcriptional and epigenetic regulation of neural gene expression, mechanisms of synaptic plasticity, protein misfolding and aggregation, neuroinflammatory cascades, and cell death pathways in neurodegenerative conditions. Additionally, we encourage submissions addressing the roles of non-coding RNAs, exosomes, ion channels, mitochondrial dysfunction, and the molecular basis of neuron–glia interactions.

This Special Issue also welcomes advances in cutting-edge methodologies—such as single-cell omics, CRISPR-based genome editing, optogenetics, and molecular imaging techniques—that provide new windows into the complexity of the nervous system at molecular resolution. Furthermore, we encourage translational studies that bridge molecular mechanisms with clinical applications, including biomarker discovery, drug development, and therapeutic strategies for neurodegenerative and neurodevelopmental disorders.

As we reflect on the progress made since the founding of IJMS, we look forward to contributions that not only celebrate past achievements but also illuminate emerging trends and critical challenges in molecular neurobiology. We invite researchers from basic science, clinical neuroscience, bioengineering, and related fields to join us in marking this milestone and shaping the future of brain research.

Prof. Dr. Kiminobu Sugaya
Guest Editor

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Keywords

molecular neurobiology
neural signaling and gene regulation
synaptic plasticity
neurodevelopment
neurodegeneration
neuroregeneration
neuroinflammation
epigenetics in neuroscience
non-coding RNAs
protein misfolding and aggregation
exosomes and extracellular vesicles
stem cells and neural repair
biomarkers of neurological disease
translational neuroscience
neuropharmacology
brain omics (genomics, proteomics, transcriptomics)
neuronal-glial interactions
mitochondrial dysfunction in the nervous system

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Published Papers (9 papers)

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Research

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35 pages, 3522 KB

Open AccessArticle

The Mechanism of LTX^N4C-Induced Ca²⁺ Influx Involves Latrophilin-Mediated Activation of Ca_v2.x Channels

by Jennifer K. Blackburn, John-Paul Silva, Evelina Petitto, Dietmar Cholewa, Elizaveta Fasler-Kan, Kirill E. Volynski and Yuri A. Ushkaryov

Int. J. Mol. Sci. 2025, 26(22), 11200; https://doi.org/10.3390/ijms262211200 - 19 Nov 2025

Viewed by 355

Abstract

Store-operated Ca²⁺ entry (SOCE) is a key regulator of cytosolic Ca²⁺ (Ca²⁺_cyt). Presynaptic SOCE can be activated by ligands like α-latrotoxin, which acts through the presynaptic G-protein-coupled receptor latrophilin-1 (LPHN1), inducing Ca²⁺ influx and neurotransmitter release. To understand how SOCE-associated proteins contribute to LPHN1 signaling in neurons, we used mouse neuroblastoma NB2a cells as a genetically tractable neuronal model. The cells were stably transfected with exogenous LPHN1 or its non-signaling mutant and stimulated with the non-pore-forming α-latrotoxin mutant LTX^N4C, a known trigger of neurotransmitter release. LPHN1 expression increased the proportion of neuron-like cells and upregulated the voltage-gated Ca²⁺ channels Ca_v1.2 and Ca_v2.1. LPHN1 stimulation by LTX^N4C induced a small Ca²⁺ release sensitive to thapsigargin, and a strong, gradual influx of Ca²⁺, which was insensitive to thapsigargin. Single-cell imaging revealed that this influx consisted of desynchronized high-amplitude Ca²⁺ oscillations in individual cells. This response was reduced by Orai2 knockdown and completely blocked by the Ca_v2.1/2.2 inhibitor ω-conotoxin MVIIC. We conclude that LPHN1 activation by LTX^N4C primes Ca²⁺ stores and induces the opening of Ca_v2.1/2.2 channels. These channels mediate an initial Ca²⁺ influx that triggers Ca²⁺-induced Ca²⁺ release and SOCE. This mechanism, elucidated in model cells, can explain how LTX^N4C stimulates neurotransmitter release. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

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24 pages, 5090 KB

Open AccessArticle

PAC1 Receptor Knockout Mice Reveal Critical Links Between ER Stress, Myelin Homeostasis, and Neurodegeneration

by Minduli Withana, Laura Bradfield, Margo I. Jansen, Giuseppe Musumeci, James A. Waschek and Alessandro Castorina

Int. J. Mol. Sci. 2025, 26(17), 8668; https://doi.org/10.3390/ijms26178668 - 5 Sep 2025

Viewed by 1475

Abstract

The pituitary adenylate cyclase-activating polypeptide receptor 1 (PAC1) plays a pivotal role in central nervous system development and homeostasis. Comparisons of PAC1 knockout (PAC1^−/−), heterozygous (PAC1^+/−) and wild-type (PAC1^+/+) mice demonstrate that PAC1 deficiency severely impairs pre-weaning survival and results in marked developmental deficits, including reduced postnatal weight and altered locomotor behavior. PAC1^−/− mice exhibited hyperlocomotion, reduced anxiety-like behavior, and transient deficits in motor coordination. Gene expression analyses revealed widespread dysregulation of oligodendrocyte-associated markers, with significant myelin reduction and decreased mature oligodendrocyte density in the corpus callosum. ER stress was evidenced in both white matter and motor cortex, as indicated by altered expression of UPR-related genes and increased phosphorylated (p)IRE1⁺ neurons. Retinal morphology was compromised in PAC1^−/− animals, with reduced overall retinal and ganglion cell layer thickness. Notably, no gross morphological or molecular abnormalities were detected in the spinal cord regarding myelin content or MBP expression; however, synaptic marker expression was selectively reduced in the ventral horn of PAC1-deficient mice. Together, these findings highlight a critical role for PAC1 in oligodendrocyte maturation, retinal development, and synaptogenesis, providing new insights with relevance in multiple sclerosis and other neurodevelopmental and neurodegenerative conditions. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

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18 pages, 1615 KB

Open AccessArticle

Spectroscopic Profile of Metabolome Dynamics During Rat Cortical Neuronal Differentiation

by Idália Almeida, Filipa Martins, Brian J. Goodfellow, Alexandra Nunes and Sandra Rebelo

Int. J. Mol. Sci. 2025, 26(16), 8027; https://doi.org/10.3390/ijms26168027 - 20 Aug 2025

Viewed by 695

Abstract

Neuronal differentiation is a highly dynamic process marked by coordinated biochemical, structural, and metabolic changes. Rat primary cortical neurons are the preferred cell model to study this process as they can maintain their functional attributes, including functional synapses, and simulate the behavior of neuronal cells in vivo. In this study, we employed Fourier transform infrared (FTIR) spectroscopy to monitor the molecular transformations that occur during the differentiation of rat cortical neurons. Partial least squares regression (PLS-R) analysis from the 1800–1500 cm⁻¹ region further allows the identification of the spectroscopic profile of early and late differentiation stages, highlighting the technique’s ability to detect subtle molecular changes. Further peak intensity analysis revealed significant changes in the cells’ metabolome during differentiation; it was possible to observe remodeling of protein secondary structures and an increase in protein phosphorylation levels, which can imply activation of signaling pathways essential for neuronal differentiation and maturation. Concomitantly, lipid-associated spectral regions demonstrated increased levels of total lipids, lipid esters, and longer acyl chains and decreased unsaturation levels, alterations that can be linked to membrane expansion throughout neuronal differentiation. These findings underscore FTIR spectroscopy as a valuable tool for studying neuronal differentiation, offering insights into the conformational and metabolic shifts underlying the formation of mature neuronal phenotypes. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

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13 pages, 1848 KB

Open AccessArticle

Expression of Dynorphin and Kappa-Opioid Receptors in the Bed Nucleus of the Stria Terminalis: Focus on Adolescent Development

by Albert R. Gradev, Pavel I. Rashev, Dimitrinka Y. Atanasova, Angel D. Dandov and Nikolai E. Lazarov

Int. J. Mol. Sci. 2025, 26(16), 7955; https://doi.org/10.3390/ijms26167955 - 18 Aug 2025

Viewed by 1228

Abstract

The bed nucleus of the stria terminalis (BNST) is a heterogeneous and complex limbic forebrain structure, which plays an important role in drug addiction and anxiety. Dynorphin and kappa-opioid receptors (DYN/KOR) comprise a crucial neural system involved in modulating stress-induced drug and alcohol addiction. Previous studies have highlighted the BNST as a brain region with a strong DYN/KOR expression. However, no research has been conducted on the adolescent plasticity of this system. In the present study, we used 20- and 60-day-old Wistar rats to reveal the adolescent dynamics and possible sex differences of the DYN/KOR system in certain BNST nuclei associated with addiction behavior. We found a low expression of DYN in neuronal perikarya and a significant increase in DYN-containing nerve fibers in the lateral posterior and lateral dorsal nuclei of the rat BNST. In addition, an enhanced expression of KORs was observed in the examined BNST subnuclei with some sex differences favoring females, thus highlighting the importance of considering critical developmental differences between sexes in research. The dynamics of the DYN/KOR system observed in this study may help to explain the increased vulnerability of adolescents for developing drug and alcohol addiction. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

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17 pages, 3248 KB

Open AccessArticle

Interneuron-Driven Ictogenesis in the 4-Aminopyridine Model: Depolarization Block and Potassium Accumulation Initiate Seizure-like Activity

by Elena Yu. Proskurina, Julia L. Ergina and Aleksey V. Zaitsev

Int. J. Mol. Sci. 2025, 26(14), 6812; https://doi.org/10.3390/ijms26146812 - 16 Jul 2025

Viewed by 975

Abstract

The mechanisms of ictal discharge initiation remain incompletely understood, particularly the paradoxical role of inhibitory fast-spiking interneurons in seizure generation. Using simultaneous whole-cell recordings of interneurons and pyramidal neurons combined with extracellular [K⁺]_o monitoring in mouse entorhinal cortex-hippocampal slices (4-aminopyridine model of epileptiform activity), we identified a critical transition sequence: interneurons displayed high-frequency firing during the preictal phase before entering depolarization block (DB). DB onset coincided with the peak of rate of extracellular [K⁺] accumulation. Pyramidal cells remained largely silent during interneuronal hyperactivity but started firing within 1.1 ± 0.3 s after DB onset, marking the transition to ictal discharges. This consistent sequence (interneuron DB → [K⁺]_o rate peak → pyramidal cell firing) was observed in 100% of entorhinal cortex recordings. Importantly, while neurons across all entorhinal cortical layers synchronously fired during the first ictal discharge, hippocampal CA1 neurons showed fundamentally different activity: they generated high-frequency interictal bursts but did not participate in ictal events, indicating region-specific seizure initiation mechanisms. Our results demonstrate that interneuron depolarization block acts as a precise temporal switch for ictogenesis and suggest that the combined effect of disinhibition and K⁺-mediated depolarization triggers synchronous pyramidal neuron recruitment. These findings provide a mechanistic framework for seizure initiation in focal epilepsy, highlighting fast-spiking interneurons dysfunction as a potential therapeutic target. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

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Review

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15 pages, 476 KB

Open AccessReview

Incretin Mimetics as Potential Therapeutics for Concussion and Traumatic Brain Injury: A Narrative Review

by Samuel Sipos, Mirjana Jerkic, Ori D. Rotstein and Tom A. Schweizer

Int. J. Mol. Sci. 2026, 27(1), 45; https://doi.org/10.3390/ijms27010045 - 20 Dec 2025

Viewed by 126

Abstract

Traumatic brain injury (TBI) represents a significant health concern, with an estimated 70 million annual cases worldwide. Mild brain trauma (concussions) is the most common TBI (81%), followed by moderate (11%) and severe (8%). Cytokine release and neuroinflammation after TBI may cause blood–brain barrier and tissue damage, triggering unfavorable outcomes, including disabilities and mortality. Current TBI treatments, focused on preventing secondary injury, are limited and insufficient. Therefore, new therapeutic approaches are necessary. A growing body of recent literature supports the potential use of incretins: glucagon-like peptide-1, glucose-dependent insulinotropic peptide, and glucagon receptor agonists, as potent neurotrophic/neuroprotective agents. Experiments performed in cellular and animal models, and a limited number of clinical studies, provide evidence that incretins might be a novel and effective treatment for TBI. Incretin-based compounds have already been shown to be safe and efficacious for the treatment of type 2 diabetes mellitus in humans. Therefore, incretins are ideal candidates for rapid evaluation in clinical trials of TBI and might become a novel therapeutic tool for a condition that has very few disease modifying treatments available. Well-designed human clinical trials are urgently needed to determine optimal dosing, timing, and patient selection for effective incretin use in concussion and TBI. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

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13 pages, 588 KB

Open AccessReview

Efficacy and Tolerability of Bupropion in Major Depressive Disorder with Comorbid Anxiety Symptoms: A Systematic Review

by Mario Pinzi, Alessandro Cuomo, Despoina Koukouna, Giacomo Gualtieri, Caterina Pierini, Maria Beatrice Rescalli, Simone Pardossi, Benjamin Patrizio and Andrea Fagiolini

Int. J. Mol. Sci. 2025, 26(24), 11767; https://doi.org/10.3390/ijms262411767 - 5 Dec 2025

Viewed by 1082

Abstract

Anxiety symptoms are highly prevalent in major depressive disorder (MDD) and are associated with greater severity, functional impairment, and poorer treatment outcomes. Bupropion is widely used in clinical practice and is generally considered to have a favorable tolerability profile, but its effects on comorbid anxiety remain uncertain. We conducted a PRISMA-guided systematic review of randomized controlled trials, pooled analyses, and open-label comparative studies evaluating bupropion in adults with MDD and clinically significant anxiety symptoms. Searches of PubMed, Scopus and Web of Science were performed through August 2025. Outcomes included validated measures of anxiety and depressive symptoms and reported tolerability. Risk of bias was assessed using RoB 2 and ROBINS-I, and certainty of evidence was evaluated using GRADE. Six studies (n ≈ 3700) met inclusion criteria. Anxiety was a predefined secondary outcome in some trials and a post hoc or exploratory measure in others. Across designs, bupropion was generally associated with improvements in anxiety and depressive symptoms on secondary or exploratory anxiety measures. In pooled patient-level analyses, SSRIs showed a modest advantage over bupropion in patients with high baseline anxiety, whereas individual randomized and open-label studies found no significant between-group differences. None of the included studies reported a clear signal of anxiety worsening with bupropion on the anxiety measures used. Tolerability findings indicated a lower risk of sexual dysfunction with bupropion compared with SSRIs, while insomnia occurred more frequently but was generally manageable. Low-certainty evidence suggests that bupropion may provide clinically relevant improvement in anxiety symptoms in adults with MDD, with generally comparable efficacy to SSRIs in most presentations but a modest SSRI advantage in highly anxious subgroups. Interpretation should consider that anxiety outcomes were often secondary or exploratory and that several studies were at risk of bias. Well-designed randomized trials with anxiety as a primary endpoint are needed. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

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26 pages, 1700 KB

Open AccessReview

Multisystemic Impact of RNF213 Arg4810Lys: A Comprehensive Review of Moyamoya Disease and Associated Vasculopathies

by Eva Bagyinszky, YoungSoon Yang and Seong Soo A. An

Int. J. Mol. Sci. 2025, 26(16), 7864; https://doi.org/10.3390/ijms26167864 - 14 Aug 2025

Cited by 2 | Viewed by 2909

Abstract

The ring finger protein 213 (RNF213) Arg4810Lys variant has been previously identified as a significant risk factor for Moyamoya disease (MMD), particularly in East Asian populations. This review explores the broader impact of the Arg4810Lys mutation on various cerebrovascular conditions, including Moyamoya syndrome (MMS), intracranial artery stenosis, quasi-Moyamoya syndromes, ischemic stroke, and intracranial atherosclerosis. Beyond the brain, it is also implicated in pulmonary arterial hypertension, coronary artery disease, and renal artery stenosis, emphasizing its systemic effects. Functional studies suggest that RNF213 Arg4810Lys alters angiogenic signaling, endothelial cell function, vascular remodeling, and immune response pathways, especially when influenced by environmental stressors, like hypoxia or inflammation. The gene dosage of Arg4810Lys significantly affects disease phenotypes, with homozygous carriers typically experiencing earlier onset with increased severe symptoms. The variant also exhibits incomplete penetrance and frequently co-occurs with additional genetic alterations, including trisomy, KIF1A, FLNA, and PCSK9 mutations, which complicates its pathogenicity. A comprehensive understanding of RNF213 Arg4810Lys’s systemic impact is essential to developing effective risk assessment strategies, personalized treatments, and targeted therapies for associated vascular diseases. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

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38 pages, 1540 KB

Open AccessReview

Understanding the Pre-Clinical Stages of Parkinson’s Disease: Where Are We in Clinical and Research Settings?

by Camilla Dalla Verde, Sri Jayanti, Korri El Khobar, John A. Stanford, Claudio Tiribelli and Silvia Gazzin

Int. J. Mol. Sci. 2025, 26(14), 6881; https://doi.org/10.3390/ijms26146881 - 17 Jul 2025

Cited by 1 | Viewed by 3256

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the world. PD is characterized by motor and non-motor symptoms, but the diagnosis primarily relies on the clinical assessment of postural and movement abnormalities, supported by imaging and genetic testing. It is widely accepted that the disease process begins decades before the onset of overt symptoms. Emerging evidence suggests that neuroinflammation plays a central role in the pathogenesis of PD, particularly during the pre-clinical phase. Activated microglia, increased levels of pro-inflammatory cytokines, and persistent oxidative stress have all been associated with the gradual loss of dopaminergic neurons. Although earlier detection and diagnosis remain elusive, achieving these goals is crucial for advancing prevention and disease-modifying strategies. Clinical studies are ongoing. To fill the gap, research models that recapitulate the chronic disease progression of PD are crucial to test preventive and disease-modifying strategies. This review briefly summarizes clinical knowledge on PD as a starting point for improving research models. Furthermore, we will critically evaluate how the existing models have been utilized and highlight opportunities to overcome their limitations and enhance the translational relevance to clinical application. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)

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