{"title":"Reduction of the Ca<sup>2+</sup> permeability of ligand-gated ion channels as a strategy against excitotoxicity.","authors":"Tiziano D'Andrea, Sergio Fucile","doi":"10.3389/fncel.2025.1617006","DOIUrl":"10.3389/fncel.2025.1617006","url":null,"abstract":"<p><p>Excitotoxic damage is due to an excessive Ca<sup>2+</sup> entry in cells following overactivation of Ca<sup>2+</sup>-permeable ion channels. In neurons, Ca<sup>2+</sup>-dependent excitotoxicity is linked to the prominent activation of N-Methyl-d-Aspartate receptors (NMDARs), exhibiting a high permeability to Ca<sup>2+</sup>. Different neurodegenerative diseases share glutamate-and NMDAR-dependent excitotoxicity as a pathogenic mechanism, but also different ligand-gated ion channels (LGICs) may be involved in excitotoxic-related pathologies, such as muscle nicotinic acetylcholine receptor in some forms of congenital myasthenic syndrome. We posit that excitotoxicity due to the overactivation of Ca<sup>2+</sup>-permeable LGICs may be counteracted by using molecules able to reduce selectively the Ca<sup>2+</sup> entry, without blocking Na<sup>+</sup> influx, thus reducing the adverse effects induced by channel blockers. In this review, we recapitulate: (i) the techniques used to quantify the Ca<sup>2+</sup> permeability of LGICs, with a particular focus on the fractional Ca<sup>2+</sup> current (P<sub>f</sub>, i.e., the percentage of the total current carried by Ca<sup>2+</sup>); (ii) the known Pf values of the main LGICs; (iii) the modulation of the LGIC P<sub>f</sub> values induced by drugs and measured to date. These data support the possibility of fighting excitotoxicity-related pathologies with a new therapeutic approach.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1617006"},"PeriodicalIF":4.0,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12307407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Monokesh K Sen, Keagan Dunville, Nicole Miles, Michelle Newbery, Neville S Ng, Lezanne Ooi
{"title":"Editorial: Recent advances in mitochondrial dysfunction and therapeutics for neurodegeneration and aging.","authors":"Monokesh K Sen, Keagan Dunville, Nicole Miles, Michelle Newbery, Neville S Ng, Lezanne Ooi","doi":"10.3389/fncel.2025.1650938","DOIUrl":"10.3389/fncel.2025.1650938","url":null,"abstract":"","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1650938"},"PeriodicalIF":4.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12303997/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Enrico Cherubini, Arianna Maffei, Egidio D'Angelo, Dirk M Hermann, Marie-Ève Tremblay, Christian Hansel
{"title":"Editorial: Paradigm shifts and innovations in cellular neuroscience.","authors":"Enrico Cherubini, Arianna Maffei, Egidio D'Angelo, Dirk M Hermann, Marie-Ève Tremblay, Christian Hansel","doi":"10.3389/fncel.2025.1644329","DOIUrl":"10.3389/fncel.2025.1644329","url":null,"abstract":"","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1644329"},"PeriodicalIF":4.0,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12301337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144729287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Mechanosensitive Piezo1 channel: an emerging target in demyelination disease.","authors":"Yuxi Zhang, Xiaoke Yang, Simin Deng, Chenxu Wang, Jialing Hu, Qinghai Lan","doi":"10.3389/fncel.2025.1556892","DOIUrl":"10.3389/fncel.2025.1556892","url":null,"abstract":"<p><p>Many physiological processes in the human body are initiated by mechanical signals, which are transmitted via ion channels. Piezo-type mechanosensitive ion channel component 1 (Piezo1) is a protein highly expressed in the brain, playing a critical role in sensing changes in the mechanical microenvironment. Extensive research has demonstrated that Piezo1 is an essential component for generating currents in mechanically activated cation channels. It is involved in several key processes in the nervous system, including neuronal development and differentiation, nerve regeneration, axon guidance, and myelination. Demyelinating diseases, characterized by the loss of nerve myelin sheaths, occur in the central or peripheral nervous system. These diseases are clinically challenging due to their diverse etiologies, multiple types, poor prognosis, and lack of definitive cures. This article aims to review the current research on the role of Piezo1 in myelination and its involvement in demyelinating diseases, as well as to explore the potential of targeting Piezo1 for therapeutic interventions in such conditions.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1556892"},"PeriodicalIF":4.2,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12283589/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144698029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Emmanuel Ojo, Temitope Adu, Raheem F H Ai Aameri, Shelley A Tischkau
{"title":"AhR regulation of amyloid beta-induced inflammation in astrocyte cells.","authors":"Emmanuel Ojo, Temitope Adu, Raheem F H Ai Aameri, Shelley A Tischkau","doi":"10.3389/fncel.2025.1618209","DOIUrl":"10.3389/fncel.2025.1618209","url":null,"abstract":"<p><strong>Introduction: </strong>Amyloid beta (Aβ) plaques, tau tangles, and neuroinflammation are common features present in Alzheimer's Disease (AD), and glial cells are essential mediators of the inflammatory reaction. Aryl hydrocarbon receptor (AhR), a transcription factor engaged in regulation of immune function, may be involved in the pathogenesis of AD, through modulation of neuroinflammation. This study explores how AhR affects astrocyte function in response to inflammatory stimuli, with emphasis on Aβ.</p><p><strong>Methods and results: </strong>In primary hippocampal astrocyte cultures from wild type (WT, C57BL6/J) or AhR germline knockout (AhRKO) mice, pretreatment with the AhR agonist, 6-Formylindolo[3,2-b] carbazole (FICZ), attenuated Aβ-induction of reactive astrocyte development, characterized by decreased astrocyte complement C3 expression and decreased proinflammatory cytokine release. In addition, Aβ exposure exacerbated TNF-a cytokine release and increased GFAP immunoreactivity in astrocytes derived from AhRKO mice. In response to Aβ injection into the mouse hippocampus <i>in vivo</i>, AhRKO mice demonstrated increased astrocyte hypertrophy, reinforcing AhR function in regulating astrocyte responses to neuroinflammation.</p><p><strong>Discussion: </strong>These findings suggest that AhR activation in astrocytes attenuates development of the neuroinflammatory state, and identifies AhR as an interesting therapeutic target to mitigate neuroinflammation and the progression of AD.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1618209"},"PeriodicalIF":4.2,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12279702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144689700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Broccoli for the brain: a review of the neuroprotective mechanisms of sulforaphane.","authors":"Riley N Bessetti, Karen A Litwa","doi":"10.3389/fncel.2025.1601366","DOIUrl":"10.3389/fncel.2025.1601366","url":null,"abstract":"<p><p>Sulforaphane, a phytochemical abundant in the sprouts of cruciferous vegetables, protects plants during a critical period of development. Through sulforaphane's ability to activate the mammalian Nuclear Factor Erythroid 2-related Factor 2 (NRF2) pathway, these beneficial properties extend beyond plants. Our current review explores emerging neuroprotective mechanisms of sulforaphane and their relation to neurological disorders. Primarily, we discuss the ability of sulforaphane to mitigate oxidative stress and prevent neuroinflammation. Given sulforaphane's ability to activate multiple cytoprotective mechanisms, sulforaphane is emerging as a promising therapeutic for multiple neurodegenerative and neurodevelopmental disorders. In this review, we highlight current clinical trials in neurological disorders and conclude by discussing therapeutic opportunities and challenges for sulforaphane. Together, preclinical models and clinical trials highlight emerging themes of sulforaphane-mediated neuroprotection, including hormetic responses that depend upon the cell/tissue, neurological condition, insult, and developmental stage. In particular, low sulforaphane doses consistently exhibit beneficial effects in preclinical neuronal cell cultures models and avoid cytotoxic effects of higher sulforaphane doses. These factors will be important considerations in informing therapeutic use of sulforaphane.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1601366"},"PeriodicalIF":4.2,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12271217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144674238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Caitlyn A Chapman, Nadya Povysheva, Tyler B Tarr, Jessica L Nuwer, Stephen D Meriney, Jon W Johnson, Tija C Jacob
{"title":"Chronic benzodiazepine treatment triggers gephyrin scaffold destabilization and GABA<sub>A</sub>R subsynaptic reorganization.","authors":"Caitlyn A Chapman, Nadya Povysheva, Tyler B Tarr, Jessica L Nuwer, Stephen D Meriney, Jon W Johnson, Tija C Jacob","doi":"10.3389/fncel.2025.1624813","DOIUrl":"10.3389/fncel.2025.1624813","url":null,"abstract":"<p><p>Benzodiazepines (BZDs) are important clinical drugs with anxiolytic, anticonvulsant, and sedative effects mediated by potentiation of inhibitory GABA type A receptors (GABA<sub>A</sub>Rs). Tolerance limits the clinical utility of BZDs, yet the mechanisms underlying tolerance after chronic exposure have not been thoroughly investigated. Here, we assessed the impact of chronic (7-day) treatment with the BZD diazepam (DZP) on the dynamic plasticity and subsynaptic organization of the gephyrin scaffold and γ2 subunit-containing GABA<sub>A</sub>Rs in primary neurons. After functional confirmation of diminished BZD sensitivity, we provide the first super-resolution analysis of inhibitory nanoscale plasticity induced by chronic BZD exposure: gephyrin subsynaptic domains were smaller and the inhibitory postsynaptic area was overall diminished by DZP treatment, resulting in a condensation of synaptic γ2-GABA<sub>A</sub>Rs into smaller synaptic areas. Using a novel fluorescence-based <i>in situ</i> proximity ligation assay and biochemical fractionation analysis, the mechanism for gephyrin downregulation was revealed to be dependent on phosphorylation and protease cleavage. Accordingly, DZP treatment impaired gephyrin synaptic stability, demonstrated by live-imaging photobleaching experiments. Despite the loss of BZD sensitivity and stable synaptic gephyrin, 7-day DZP treatment did not reduce the surface or total protein levels of BZD-sensitive γ2-GABA<sub>A</sub>Rs, as shown in prior short-term BZD treatment studies. Instead, chronic DZP treatment induced an accumulation of γ2-GABA<sub>A</sub>Rs in the extrasynaptic membrane. Surprisingly, γ2-GABA<sub>A</sub>R interactions with gephyrin were also enriched extrasynaptically. An identified rise in extrasynaptically-localized gephyrin cleavage fragments may function to confine receptors away from the synapse, as supported by a decrease in extrasynaptic γ2-GABA<sub>A</sub>R mobility. Altogether, we find that chronic BZD treatment triggers several subtle converging plasticity events at inhibitory synapses which effectively restrict the synaptic renewal of BZD-sensitive GABA<sub>A</sub>Rs via mechanisms distinct from those observed with short-term treatment.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1624813"},"PeriodicalIF":4.2,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12271172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144674239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Tear deficiency transforms spatial distribution of corneal calcitonin gene-related peptide-positive nerves in rats.","authors":"Takeshi Kiyoi, Akihiro Nakajima, Qiang He, Li Liu, Shijie Zheng, Shizuka Kobayashi, Junsuke Uwada, Takayoshi Masuoka","doi":"10.3389/fncel.2025.1619310","DOIUrl":"10.3389/fncel.2025.1619310","url":null,"abstract":"<p><p>The nerve terminals distributed in the cornea are important for sensory perception and the maintenance of ocular surface homeostasis. In dry eye disease (DED), corneal nerves undergo functional and morphological changes that may be involved in abnormal ocular surface sensation and corneal pathology. However, changes in the spatial distribution of corneal nerves, including polymodal nociceptors, and their regulatory mechanisms remain unknown. In the present study, we analyzed time-dependent changes in corneal nerves, focusing on calcitonin gene-related peptide (CGRP)-positive nociceptive nerves in DED model rats, in which both the extraorbital and intraorbital lacrimal glands were surgically excised. After gland excision, the cornea showed acute inflammation, characterized by the presence of segmented-nucleus neutrophil infiltration, followed by chronic inflammation and angiogenesis. In parallel, denervation and subsequent reinnervation in the epithelium, as well as excessive innervation in the stroma, were observed, both involving CGRP-positive nerves. The DED rats showed hypoesthesia and subsequently hyperesthesia in response to mechanical stimulation of the corneal surface, which was synchronized with the denervation and reinnervation of corneal nerve plexuses in the epithelium. Persistent hyperalgesia to capsaicin in DED rats was not correlated with CGRP-positive nerve distribution in the early phase. After gland excision, the expression of neurotropic factor Sema7A increased within the epithelium and stroma, while that of the repulsive axon guidance factor Sema3A decreased in the epithelium. The expression patterns of these molecules correlate with reinnervation of the epithelium and excessive innervation of the stroma. These data suggest that changes in nerve distribution, including CGRP-positive nerves, might partially contribute to sensory perception and progression of corneal inflammatory pathology in DED. Sema3A and Sema7A may be involved in reinnervation as part of the regulatory mechanism in DED.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1619310"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Potassium channel clustering: mechanisms shaping axonal excitability.","authors":"Gabriel Escobedo, Matthew N Rasband","doi":"10.3389/fncel.2025.1627517","DOIUrl":"10.3389/fncel.2025.1627517","url":null,"abstract":"<p><p>The precise clustering of ion channels at axon initial segments (AIS) and nodes of Ranvier is essential for axonal excitability and rapid action potential propagation. Among the axonal ion channels, voltage-gated potassium channels (Kv) and two-pore domain potassium (K2P) leak channels are key regulators of AIS and nodal excitability. Kv7 and Kv1 channels contribute to action potential threshold and repolarization at the AIS, and membrane repolarization in axons has historically been attributed to Kv channels. However, recent studies suggest that at nodes of Ranvier K2P channels, particularly TRAAK and TREK-1, play a dominant role in action potential repolarization. The interaction of Kv and K2P channels with diverse scaffolding proteins ensures their precise localization at AIS and nodes. Mislocalization or dysfunction of axonal Kv and K2P channels can cause epilepsy and neurodevelopmental disorders. This review explores the diversity of potassium channels and the mechanisms responsible for their clustering at AIS and nodes of Ranvier. Understanding these processes will be essential for therapeutic strategies aimed at treating diseases characterized by abnormal potassium channel expression, clustering, and function in neurons.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1627517"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12259577/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Circulating exosomes with unique lipid signature in relapsing remitting multiple sclerosis.","authors":"Claudia Palazzo, Ilaria Asci, Silvia Russo, Cinzia Buccoliero, Vincenzo Mangialardi, Pasqua Abbrescia, Onofrio Valente, Maddalena Ruggieri, Damiano Paolicelli, Simona Lobasso, Antonio Frigeri","doi":"10.3389/fncel.2025.1613618","DOIUrl":"10.3389/fncel.2025.1613618","url":null,"abstract":"<p><p>Exosomes are small, membrane-bound vesicles secreted by most cell types into the extracellular environment. They play a crucial role in intercellular communication by transporting bioactive molecules, including proteins, lipids, and RNAs, thereby influencing the phenotype and potentially the genotype in recipient cells. In recent years, exosomes have gained increasing attention in the study of pathophysiological conditions and numerous diseases, including multiple sclerosis (MS), an autoimmune disorder with myelin sheath and neuroaxonal damage in the central nervous system. In this study, we isolated and purified serum-derived exosomes from patients with relapsing remitting MS (RR-MS) and characterized their lipid profiles using matrix-assisted laser desorption ionization-time-of-flight/mass spectrometry (MALDI-TOF/MS). Lipid analysis was performed in both negative and positive ion modes on intact exosomes, bypassing lipid extraction steps and significantly reducing sample-processing time. The lipid profiles of RR-MS exosomes were compared to those of exosomes isolated from the serum of healthy subjects (HS), and statistical analysis was applied to mass spectra to identify potential lipid biomarkers. The specific phospholipid marker of exosomal membranes, bis(monoacylglycero)phosphate (BMP), was clearly detected in both MALDI lipid profiles, with no significant differences in its content between the two sample groups. However, RR-MS exosomes exhibited significantly lower levels of phosphatidic acid (PA) compared to HS exosomes, despite PA being a key structural component of extracellular vesicles. Notably, comparative analysis revealed an enrichment of several lysophosphatidylcholine (LPC) species in RR-MS exosome membranes, aligning with their known proinflammatory role in MS pathology. Our most significant finding was a markedly lower phosphatidylcholine (PC) to LPC ratio in the pathological group indicating potential alterations in membrane lipid homeostasis. To the best of our knowledge, this study is the first to report a distinct lipid signature in serum-derived exosomes from RR-MS patients using direct MALDI-TOF/MS analysis.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"19 ","pages":"1613618"},"PeriodicalIF":4.2,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12245768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}