Frontiers In Cellular Neuroscience[JOURNAL]
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200 papers
Molecular mechanisms underlying the ferroptosis-induced epileptiform activity in mouse cortical slices.
Petrillo S, Loia F, Giustizieri M … +9 more , Torda C, Cairoli S, Goffredo B, Trivisano M, de Palma L, Vigevano F, Specchio N, Cherubini E, Piemonte F
Front Cell Neurosci · 2026 · PMID 41822170 · Full text
INTRODUCTION: Ferroptosis, a newly defined iron-dependent programmed cell death, characterized by excessive accumulation of lipid peroxides and reactive oxygen species, is involved in epilepsy, particularly in those form...
INTRODUCTION: Ferroptosis, a newly defined iron-dependent programmed cell death, characterized by excessive accumulation of lipid peroxides and reactive oxygen species, is involved in epilepsy, particularly in those forms resistant to drugs. In a previous study, we have demonstrated that exposure of mouse cortical slices to the ferroptosis inducer RSL-3, induces interictal epileptiform discharges. To investigate the mechanisms underlying ferroptosis-induced epileptic activity in RSL-3-treated cortical slices, we analysed the expression of the main contributors to ferroptosis susceptibility in cells. METHODS: The expression of proteins involved in RSL-3 induced ferroptosis pathways were analysed on mouse cortical slices by Western blot and qRT-PCR. The epileptogenic response was investigated by electrophysiological patch clamp recordings, in current clamp mode, from layer 2/3 mouse cortical slices. RESULTS: In cortical neurons, the ferroptosis induction by RSL-3 was associated with a reduced expression of the GPX4/GSH redox pathway, responsible for the clearance of lipid peroxides, and an upregulation of 15-LOX, which promotes the formation of lipid peroxides. Furthermore, the cysteine/glutamate antiporter Xc, a modulator of excitotoxicity in the brain, was up-regulated either after RSL-3-treatment or by incubating neurons with 4-HNE, the bioactive product of lipid peroxidation. Interestingly, 4-HNE was able to generate spontaneous interictal bursts. DISCUSSION: Our findings establish a direct link between lipid peroxidation and Xc activity. These results suggest that the xCT antiporter may represent a promising therapeutic target for treating ferroptosis-mediated drug-resistant epilepsy.
CircFRRS1 drives neuroinflammation through the miR-27a-3p/TLR4 pathway after deep hypothermic circulatory arrest.
Yan W, Wang T, Zhang S … +7 more , Zhang M, Wang J, Zhang H, Zhang J, Xie Z, Ji B, Wei C
Front Cell Neurosci · 2026 · PMID 41822169 · Full text
Neurologic injury remains a critical complication of deep hypothermic circulatory arrest (DHCA) in aortic arch surgery, with neuroinflammation driven by multiple factors in its pathogenesis. While circular RNAs (circRNAs...
Neurologic injury remains a critical complication of deep hypothermic circulatory arrest (DHCA) in aortic arch surgery, with neuroinflammation driven by multiple factors in its pathogenesis. While circular RNAs (circRNAs) are known to modulate inflammatory responses, their specific role in DHCA-associated brain injury has not been established. In this study, we demonstrated that circFRRS1 exacerbates hippocampal neuroinflammation via the miR-27a-3p/TLR4 axis through integrated and approaches. In a rat model of DHCA, machine learning-based motion sequencing (MoSeq) identified delirium-like behaviors, accompanied by hippocampal neuronal necrosis and activation of NLRP3 inflammasome. circFRRS1 was significantly upregulated in hippocampal tissue following DHCA and in hypoxic-ischemic PC-12 cells. Silencing circFRRS1 attenuated oxygen-glucose deprivation/reperfusion (OGD/R)-induced cytotoxicity and suppressed the TLR4/NF-κB/NLRP3 signaling pathway. Mechanistically, circFRRS1 acts as a molecular sponge for miR-27a-3p, thereby relieving its repression of TLR4; inhibition of miR-27a-3p abolished the observed neuroprotective effects. This study identifies circFRRS1 as the first reported circRNA to regulate DHCA-induced neuroinflammation, uncovering a novel epigenetic mechanism and suggesting the potential of circRNA-targeted therapies as adjuvants to conventional hypothermic strategies.
Microglial histone deacetylase-3 conditional deletion attenuates neurological deficits after intracerebral hemorrhage.
Watson NJ, Xu H, Sukumari-Ramesh S
Front Cell Neurosci · 2026 · PMID 41815335 · Full text
Stimulation of the innate immune system after intracerebral hemorrhage (ICH), characterized by microglial activation, contributes to ICH-induced neuroinflammation and brain damage. Despite the efficacy of broad-spectrum...
Stimulation of the innate immune system after intracerebral hemorrhage (ICH), characterized by microglial activation, contributes to ICH-induced neuroinflammation and brain damage. Despite the efficacy of broad-spectrum histone deacetylase (HDAC) inhibitors in improving acute neurological outcomes after ICH, the isoform- or cell-specific roles of histone deacetylases (HDACs) after ICH remain largely understudied. Given the emerging role of HDAC3 in various neuropathological conditions, we herein evaluate the functional role of microglial HDAC3 after ICH using newly developed microglia-specific HDAC3 conditional knockout mice (cKO). The microglia-specific conditional deletion of HDAC3 in male and female mice improved acute and long-term neurobehavioral outcomes following ICH. Furthermore, conditional deletion of HDAC3 in microglia significantly attenuated the expression of proinflammatory mediators, such as , , -, and , and augmented the expression of anti-inflammatory mediators, such as , in the ipsilateral brain region following ICH. This observation was found to be concomitant with a reduction in the number of Iba1-positive cells, further implicating attenuation of neuroinflammatory response after ICH. Moreover, conditional deletion of HDAC3 in microglia did not alter hematoma volume after ICH, suggesting that the observed effects are independent of hematoma size. Overall, the data implicate a novel role of microglial HDAC3 in regulating neurological deficits after ICH in male and female subjects.
Regional heterogeneity of striatal cholinergic interneurons: setting the stage for diverse behavioral repertoires.
Lemos JC, Duhne M, Chuhma N
Front Cell Neurosci · 2026 · PMID 41815334 · Full text
Cholinergic interneurons (ChIs) constitute only a small fraction of striatal neurons, yet their dense axonal arborizations and widespread acetylcholine release make them powerful regulators of basal ganglia output. While...
Cholinergic interneurons (ChIs) constitute only a small fraction of striatal neurons, yet their dense axonal arborizations and widespread acetylcholine release make them powerful regulators of basal ganglia output. While the striatum is often described as cytoarchitecturally uniform, accumulating evidence reveals significant regional heterogeneity in ChI properties that shape striatal computation and behavior. Recent observations suggest that ChI heterogeneity occurs at multiple levels, extending beyond simple dorsal-ventral differences. This includes morphological, electrophysiological, and molecular heterogeneity among ChIs, as well as ChI-driven behaviors in the dorsolateral striatum, dorsomedial striatum, and nucleus accumbens (core and shell). Despite these accumulating observations, most studies and reviews of ChIs focus narrowly on one or two functional levels. As a result, a systematic and comprehensive comparison of ChI activity and its modulation across finer striatal subregions and multiple levels of analysis has not been undertaken. Here, we integrate findings across cellular, circuit, and behavioral levels to frame how regional ChI heterogeneity may set the stage for diverse behavioral repertoires. In light of recent studies, we highlight ChI activity and dopamine neuron-ChI interactions and compare mechanisms of cholinergic modulation across striatal subregions. This integrative perspective reveals critical discrepancies in the current literature, which should be addressed experimentally to understand how ChIs contribute to regionally distinct behaviors in both healthy and pathological states.
Prominent astrocytic GLAST pathology occurs in newborn human and piglet hypoxic-ischemic encephalopathy: modeling relationships among laminar neuropathology, seizures, and therapeutic hypothermia.
Park D, O'Brien CE, Lee JK … +1 more , Martin LJ
Front Cell Neurosci · 2026 · PMID 41815333 · Full text
Neonatal hypoxic-ischemic encephalopathy (HIE) is frequently complicated by seizures that persist despite therapeutic hypothermia (HT), suggesting injury mechanisms insensitive to HT. Here, we tested the hypothesis that...
Neonatal hypoxic-ischemic encephalopathy (HIE) is frequently complicated by seizures that persist despite therapeutic hypothermia (HT), suggesting injury mechanisms insensitive to HT. Here, we tested the hypothesis that astrocytic glutamate-aspartate transporter (GLAST) abnormalities in the neocortex contribute to cortical hyperexcitability and seizure burden after HIE, and that HT mitigates this astrocyte-mediated mechanism. We examined the vulnerability of GLAST in the neocortex of human neonatal hypoxic-ischemic encephalopathy (HIE) and in a piglet model of hypoxia-ischemia (HI). We determined how GLAST immunoreactivity localization associates with HT outcome in clinical and experimental settings. Brain sections from postmortem human autopsy cases of term neonatal HIE and piglets (2-3 days old, = 5-6/group) were used to localize GLAST and glial fibrillary acidic proteins (GFAP) across cortical layer I-III in the somatosensory cortex. Piglets received continuous 4-channel epidural EEG recording under normothermia (NT) or mild HT (38 °C to 34 °C with rewarming; 29 h), with hypoxic-asphyxic cardiac arrest and resuscitation, or a sham procedure. Piglet survival was assessed over 7 days. Neuropathology was identified by the number of damaged neurons and GLAST puncta metrics. EEG-seizure metrics, including ictal event frequency, duration, spike-wave events, and power spectral density (PSD), were quantified using a custom seizure classification pipeline. GLAST localization in human HIE cortex was significantly abnormal compared to non-HIE control cases, characterized by perisomatic aggregation and reduced neuropil density. HI in piglets reproduced these GLAST abnormalities, including apparent aggregation, that correlated with seizure burden and neuronal pathology. HT attenuated the GLAST pathology in HI piglets at perisomatic locations to the level of sham, particularly in layers II-III, delayed seizure onset by ~24 h, and significantly reduced ictal event frequency (to lower than 5 events per 4 h) and duration (to less than 20 s per event). These findings identify prominent GLAST pathology in newborn humans and piglet HIE. HT partially restores astrocytic GLAST localization that is temporally associated with reduced seizure burden in piglets. We conclude that astrocytic glutamate transport abnormalities contribute to cortical hyperexcitability and seizures in neonatal HIE.
The neural thermostat malfunction: revisiting heatstroke through the lens of warm-sensitive neuron dysregulation.
Zhao X, Zhu J, Tang Q … +2 more , Zhu H, Liu Z
Front Cell Neurosci · 2026 · PMID 41815332 · Full text
Rising global temperatures have turned heatstroke from a seasonal concern into a year-round public health crisis, yet its underlying neuropathological mechanisms remain elusive. Central to this problem are hypothalamic w...
Rising global temperatures have turned heatstroke from a seasonal concern into a year-round public health crisis, yet its underlying neuropathological mechanisms remain elusive. Central to this problem are hypothalamic warm-sensitive neurons (WSNs), the master regulators that integrate central and peripheral thermal signals. This review synthesizes recent advances linking the molecular architecture of WSNs to heatstroke pathophysiology. Emerging evidence redefines WSNs not simply as temperature sensors, but as putative neuromodulatory hubs that may coordinate neuroinflammation, blood-brain barrier (BBB) disruption, and multi-organ failure through hypothesized neurotransmitter-cytokine crosstalk. By mapping the functional hierarchy of WSNs-from molecular thermoregulation to systemic control of thermoeffectors-this work proposes targeted neurotherapeutic strategies, offering a novel neural circuit-based framework for managing heatstroke.
Adipose-derived stem cell-conditioned medium mitigates ischemia-induced neuronal injury via the JAK1/STAT3 signaling pathway.
Huang H, Zheng M, Lai Y … +3 more , Zhang Y, Chen Y, Liu N
Front Cell Neurosci · 2026 · PMID 41809974 · Full text
INTRODUCTION: Adipose-derived stem cells (ADSCs) demonstrate therapeutic potential for ischemic stroke, primarily through paracrine actions. However, the specific intracellular signaling pathways underlying these benefit...
INTRODUCTION: Adipose-derived stem cells (ADSCs) demonstrate therapeutic potential for ischemic stroke, primarily through paracrine actions. However, the specific intracellular signaling pathways underlying these benefits remain unclear. This study investigates the critical role of JAK1/STAT3 signaling in neuroprotection mediated by ADSC-conditioned medium (ADSC-CM). METHODS: We employed a dual-model approach. rats subjected to transient middle cerebral artery occlusion (tMCAO) received intravenous ADSC-CM or vehicle at 2, 24, and 48 h post-ischemia, with or without the JAK1 inhibitor GLPG0634. Neurological function was evaluated over a period of 7 days. Subsequently, infarct volume, brain edema, neuronal survival, neurovascular regeneration, synaptic ultrastructure, mitochondrial function, and energy metabolism were analyzed. , primary cortical neurons subjected to oxygen-glucose deprivation (OGD) were treated with ADSC-CM with or without GLPG0634 to assess neurite outgrowth. Activation of the JAK1/STAT3 pathway was confirmed by Western blot in both models. RESULTS: , ADSC-CM significantly improved neurological function, reduced infarct volume and brain edema, and enhanced neuronal survival, nerve fiber regeneration, angiogenesis, synaptic plasticity, and mitochondrial function in tMCAO rats. , ADSC-CM promoted neurite outgrowth in OGD-injured neurons. Crucially, all these multifaceted neuroprotective effects were completely abolished by co-treatment with GLPG0634. Mechanistically, ADSC-CM robustly activated JAK1 and STAT3 phosphorylation in both models, an effect effectively inhibited by GLPG0634. DISCUSSION: The neuroprotective effects of ADSC-CM are mechanistically linked to the activation of the JAK1/STAT3 pathway, which mitigates ischemic damage by promoting neuronal salvage, neurovascular regeneration, synaptic plasticity, and metabolic recovery, thereby enhancing neurological functional recovery after stroke.
The dopaminergic system in neurodevelopment: preclinical models of neurodevelopmental disorders and susceptibility to neurodegeneration.
Santoni M, Mastio A, Pistis M … +1 more , Sagheddu C
Front Cell Neurosci · 2026 · PMID 41809973 · Full text
The dopaminergic system plays a pivotal role in neurodevelopment, guiding the formation and refinement of neural circuits underlying salience attribution, cognition, reward and aversion. Its maturation extends from prena...
The dopaminergic system plays a pivotal role in neurodevelopment, guiding the formation and refinement of neural circuits underlying salience attribution, cognition, reward and aversion. Its maturation extends from prenatal life through adolescence and may be influenced by genetic and environmental factors. Evidence from preclinical models suggests that perturbations during these sensitive windows may alter neurodevelopmental trajectories toward maladaptive outcomes, increasing vulnerability to neurodevelopmental disorders. This mini-review synthesizes findings from animal models to examine how physiological dopaminergic maturation might be shaped by genetic, as well as environmental, factors. We discussed maternal immune activation, prenatal cannabis exposure, and genetic models directly targeting dopaminergic function, all of which underscore the critical role of dopamine dysregulation in shaping neurodevelopmental outcomes. Beyond neurodevelopmental disorders, we extend this framework to newly emerging evidence concerning how early-life dopaminergic perturbations may influence dopamine system resilience and predispose individuals to accelerated cognitive decline and neurodegenerative disorders. Midbrain dopamine neurons exhibit intrinsic vulnerabilities that may render them especially sensitive to cumulative developmental and aging-related stressors and may serve as early predictors of disease. Finally, we discuss the therapeutic implications, emphasizing the limited mechanistic innovation in current pharmacological treatments and the growing need to target upstream or convergent developmental mechanisms in order to modify disease trajectories before overt dopaminergic dysfunction becomes established.
From Balance to Breakdown: striatal PV interneurons in Huntington's disease and Autism Spectrum Disorder.
Thabault M, Galvan L
Front Cell Neurosci · 2026 · PMID 41809972 · Full text
Once relegated to the background of striatal circuitry, parvalbumin-expressing interneurons are now emerging as central players in health and disease. Acting as true gatekeepers, striatal PV interneurons are well-describ...
Once relegated to the background of striatal circuitry, parvalbumin-expressing interneurons are now emerging as central players in health and disease. Acting as true gatekeepers, striatal PV interneurons are well-described for their role in synchronizing striatal output and balancing excitation and inhibition to sustain coordinated motor and cognitive functions. In this review, we highlight recent advances in understanding their developmental origins, molecular identity, physiological properties, and their roles in striatal function. Furthermore, we examine converging evidence implicating PV interneurons in Huntington's disease and Autism Spectrum Disorder, where their structural, molecular, and functional alterations position them at the intersection of neurodegenerative and psychiatric research.
Radial glia at the neurovascular interface during cortical development.
Al-Naama N, Pearson CA
Front Cell Neurosci · 2026 · PMID 41797835 · Full text
Radial glia are a specialized population of neural progenitor cells that persist throughout embryogenesis and into adulthood. Throughout this period, radial glia reside in a highly dynamic microenvironment that influence...
Radial glia are a specialized population of neural progenitor cells that persist throughout embryogenesis and into adulthood. Throughout this period, radial glia reside in a highly dynamic microenvironment that influences various biological decisions that govern typical cortical development. Subsequently, radial glia must fine-tune their responses to numerous environmental cues throughout development. The establishment of the cortical vasculature coincides with neurogenesis and dramatically alters the radial glia microenvironment by increasing oxygen and metabolite delivery. In addition, a synergistic spatial relationship between radial glia and endothelial cells regulates multiple aspects of radial glial biology. Here, we discuss crosstalk between radial glia and the cortical vasculature/endothelial cells throughout development, including the influence of extrinsic angiogenic processes and our growing understanding of the intricate spatial relationships between radial glia and endothelial cells.
Cochlear neural functional competence: an integrative transcriptomic module analysis of excitability, plasticity and microenvironmental support programs.
Guo L, Wang J, Gao Y … +4 more , Feng Y, Wu B, Ren X, Li Y
Front Cell Neurosci · 2026 · PMID 41797834 · Full text
BACKGROUND: Cochlear implants (CIs) restore hearing by directly stimulating spiral ganglion neurons (SGNs), yet auditory outcomes remain highly variable. Increasing evidence suggests that SGN survival alone incompletely...
BACKGROUND: Cochlear implants (CIs) restore hearing by directly stimulating spiral ganglion neurons (SGNs), yet auditory outcomes remain highly variable. Increasing evidence suggests that SGN survival alone incompletely predicts CI performance; instead, transcriptional programmes governing neuronal excitability/synaptic transmission, structural plasticity, trophic-metabolic support and injury/inflammation may better reflect neural functional competence. METHODS: We re-analysed publicly available cochlear transcriptomic datasets spanning development, adulthood and injury/degeneration. Primary resources included developmental FACS RNA-seq of hair cells and surrounding tissue, adult inner- and outer-hair-cell microarrays, and a noise-induced hearing loss (NIHL) RNA-seq cohort following mesenchymal stromal cell (MSC) therapy. We additionally analysed independent injury/degeneration datasets, including spatial transcriptomics of spiral ganglion regions after noise exposure and spiral ganglion RNA-seq after aminoglycoside-induced deafening. Guided by cochlear neuroscience literature and functional enrichment, we assembled gene modules for excitability, plasticity, trophic/metabolic support and injury/inflammation. Module activity was quantified using within-dataset standardized scores from normalized expression, avoiding cross-platform merging. We derived a Cochlear Neural Functional Competence (CNFC) score (Excitability + Trophic - Injury) and assessed robustness using a minimal 24-gene panel. External validation was performed in an independent purified SGN dataset, and CNFC was benchmarked against transcriptome-wide principal components. RESULTS: Developmental maturation was characterized by increasing excitability-associated transcripts alongside down-regulation of actin/cytoskeletal remodelling components. Adult hair cells displayed distinct trophic signatures. In the NIHL model, MSC therapy was associated with transcriptional suppression of excitatory receptor and channel genes, consistent with a shift in the injury/inflammation-excitability balance, although functional consequences remain to be established. Importantly, in independent injury/degeneration datasets, CNFC decreased in spiral ganglion neuronal regions after noise exposure and in deafened spiral ganglion. Across datasets, CNFC captured coherent trends and remained highly correlated with full-module scoring when reduced to the 24-gene panel. CONCLUSION: CNFC is a transparent, hypothesis-generating framework for summarizing cochlear neuronal functional state from transcriptomic data, complementing traditional survival metrics. By prioritizing interpretable modules and standardized within-dataset scoring, CNFC supports cross-study integration and highlights candidate programmes for mechanistic testing.
Advances in multiscale myelin imaging: from classical histology to functional insights.
Okuyama K, Komaki Y, Ishihara M … +11 more , Kurosaki Y, Tsuchiya S, Hayatsu M, Nakayama J, Uchiyama K, Itoh K, Nagai T, Shindo T, Moritoki N, Kawashima H, Shibata S
Front Cell Neurosci · 2026 · PMID 41788197 · Full text
Scientific understanding of myelin, the lipid-rich sheath of axons essential for vertebrate rapid neuronal communication, has evolved considerably. Enabled by major advances in imaging technology, research has shifted fr...
Scientific understanding of myelin, the lipid-rich sheath of axons essential for vertebrate rapid neuronal communication, has evolved considerably. Enabled by major advances in imaging technology, research has shifted from viewing myelin as a static insulator to investigating the dynamic roles of myelinating glia in nervous system development, function, and pathophysiology. This review aimed to provide a comprehensive, multi-scale overview of the imaging toolkit for myelin biology, from foundational histology to cutting-edge advances. At the macro- and meso-scales, non-invasive modalities like magnetic resonance imaging and positron emission tomography reveal myelin architecture and molecular changes, offering critical insights into large-scale pathology. At the micro-scale, advanced light microscopy now visualizes cellular dynamics and molecular interactions with remarkable clarity. Finally, at the nano-scale, sophisticated electron microscopy techniques-including volume electron microscopy and correlative approaches-resolve the ultrastructural basis of biological phenomena with unparalleled detail. As no single modality can capture the full biological context, a holistic understanding of glial biology requires the strategic integration of these multi-scale techniques with advanced computational analysis. This integrated approach is essential for revealing the full spectrum of myelin biology and uncovering novel targets for therapeutic intervention.
ACSA2 is not astrocyte-specific: implications for cell sorting strategies in the rodent brain.
Daniele E, Khelifi G, Beretta D … +6 more , Tsankov BK, Bang KWA, Beretta C, Philpott DJ, Hussein SM, Faiz M
Front Cell Neurosci · 2026 · PMID 41788196 · Full text
INTRODUCTION: Astrocyte-specific cell surface antigen-2 (ACSA2) has been established as the gold-standard marker for isolating astrocytes via magnetic-activated cell sorting (MACS) or fluorescence-activated cell sorting...
INTRODUCTION: Astrocyte-specific cell surface antigen-2 (ACSA2) has been established as the gold-standard marker for isolating astrocytes via magnetic-activated cell sorting (MACS) or fluorescence-activated cell sorting (FACS) for downstream transcriptomic studies. In a prior study of the astrocyte response to cortical stroke, we used ACSA2-based cell sorting prior to single cell RNA sequencing (scRNAseq). We found a substantial population of ACSA2 cells exhibiting robust microglial gene expression signatures, suggesting contamination of purified astrocyte preparations. METHODS: An intravenous antibody labeling strategy coupled with flow cytometry was used to determine whether contamination originated from circulating immune cells or microglia. RESULTS: Contaminating cells were identified as CNS-resident microglia that express CD45, CD11b, and ACSA2. DISCUSSION: These findings caution against the usage of ACSA2 for astrocyte purification without exclusion markers to achieve high-purity astrocyte populations for downstream multi-omics analyses.
Dual targeting of the UPS and autophagy as a novel therapy for neurodegenerative proteinopathies.
Lines G, Helley M, Gillotin S … +3 more , Brownlees J, Duce J, Smethurst P
Front Cell Neurosci · 2026 · PMID 41788195 · Full text
Neurodegenerative proteinopathies are characterized by impaired protein clearance and the accumulation of misfolded or aggregated proteins, ultimately leading to neuronal death. The two principal pathways responsible for...
Neurodegenerative proteinopathies are characterized by impaired protein clearance and the accumulation of misfolded or aggregated proteins, ultimately leading to neuronal death. The two principal pathways responsible for protein degradation in cells are the ubiquitin proteasome system (UPS) and autophagy. Emerging evidence indicates that these pathways share regulatory components and engage in extensive crosstalk. In this review, we summarize the mechanisms of the UPS and autophagy, highlight their points of interaction, and discuss therapeutic opportunities to modulate both systems in parallel to enhance protein clearance in neurodegenerative disease.
Choroid plexus organoids mimic amyloid uptake at the blood-cerebrospinal fluid-barrier.
Municio C, Sapidou K, Apsley EJ … +5 more , Fernandez-Otero M, Arber CE, Wray S, Carro E, Pellegrini L
Front Cell Neurosci · 2026 · PMID 41788194 · Full text
The choroid plexus (ChP) is a specialised tissue of the central nervous system that produces cerebrospinal fluid (CSF), maintains cerebral homeostasis and forms the blood-CSF barrier (B-CSF-B), a key interface that regul...
The choroid plexus (ChP) is a specialised tissue of the central nervous system that produces cerebrospinal fluid (CSF), maintains cerebral homeostasis and forms the blood-CSF barrier (B-CSF-B), a key interface that regulates the exchange of substances between the blood and the brain. Despite its physiological importance, the involvement of the ChP in neurodegenerative diseases such as Alzheimer's disease (AD), remains poorly understood. This is largely due to the reliance on murine models and the limited availability of human brain tissue. Recent advances in human stem-cell derived ChP organoids now offer a more physiologically relevant model to interrogate ChP role in human health and disease. Given that in AD pathology beta-amyloid (Aβ) accumulation has been linked to early disruption of brain barriers, studying the B-CSF-B is particularly relevant. Transthyretin (TTR), the predominant protein secreted by the ChP, is thought to play a role in the transport and clearance of Aβ, although its exact mechanisms are not yet fully elucidated. Here, we propose the use of ChP organoids to investigate the role of the B-CSF-B in amyloid uptake which may contribute to barrier dysfunction and disease progression in AD.
Glioinflammation: disease-associated microglia and astrocytes in psychiatric disorders, neurodegeneration, and senescence.
Uemura K, Hiro S, Attachaipanich S … +5 more , Du R, Yusof NISM, Kinoshita M, Hikosaka M, Ohtsuki G
Front Cell Neurosci · 2025 · PMID 41783158 · Full text
In this review, we synthesize recent conceptual and experimental advances in neuroscience, highlighting selected studies that delineate the roles of reactive microglia and astrocytes in the contexts of developmental infl...
In this review, we synthesize recent conceptual and experimental advances in neuroscience, highlighting selected studies that delineate the roles of reactive microglia and astrocytes in the contexts of developmental inflammatory stress, neurodegenerative diseases, and cellular senescence. Since the characterization of disease-associated glial phenotypes in 2017, building on earlier pioneering discoveries, we focus here on disease-associated microglia (DAM) and disease-associated astrocyte (DAA) to reassess their contributions to glio-inflammation. It is now recognized that the stress-induced glial states are far from uniform; however, the ontogeny, molecular determinants, and functional consequences of this heterogeneity remain incompletely understood, particularly in psychiatric disorders, Alzheimer's disease, and amyotrophic lateral sclerosis. Accordingly, we compare the glial heterogeneity and its underlying mechanisms across translational mouse models and human neuropathology, considering their evolutionary and physiological contexts. While this review does not aim to be exhaustive, we propose an integrative framework that redefines glial stress responses through the combined lenses of inflammation, transcriptomics, mitochondrial dynamics, lipid metabolism, epigenomic regulation, and cellular senescence. Finally, we outline emerging frontiers for AI-enabled multi-omic physiological and pathological approaches, emphasizing their potential to illuminate glial state transitions and accelerate therapeutic discovery in the near future.
Cholesterol depletion inhibits BDNF-dependent spike timing-dependent plasticity at thalamo-amygdala synapses.
Munsch T, Meis S, Lessmann V
Front Cell Neurosci · 2026 · PMID 41778261 · Full text
The neurotrophin brain-derived neurotrophic factor (BDNF) has emerged as a key regulator of synaptic plasticity in hippocampus and cortex of mammalian brains. In the lateral nucleus of the amygdala (LA), BDNF is involved...
The neurotrophin brain-derived neurotrophic factor (BDNF) has emerged as a key regulator of synaptic plasticity in hippocampus and cortex of mammalian brains. In the lateral nucleus of the amygdala (LA), BDNF is involved in the control of long-term potentiation (LTP). Here, we show that BDNF is involved in spike-timing dependent potentiation (STDP) of thalamic inputs onto LA projection neurons. Inhibition of BDNF/TrkB signaling with the TrkB scavenger TrkB/FC completely blocked this timing-dependent form of LTP (t-LTP). Disruption of lipid-rafts by depletion of cholesterol from synaptic microdomains with Methyl-β-cyclodextrin (MCD) also prevented induction and expression of t-LTP. These data suggest that BDNF-induced TrkB translocation into synaptic lipid-rafts is required for induction of t-LTP at thalamo-amygdala synapses. Since cholesterol-dependent modulation is not unique for TrkB receptor signaling but has been described for other receptors and ion channels involved in synaptic plasticity, additional studies are required to obtain a more complete picture regarding their role in t-LTP at thalamo-amygdala afferents.
Chemogenetic Schwann cell activation impairs early myelination and triggers adult demyelination in the peripheral nervous system.
Corral JG, Cheli VT, Santiago-Gonzalez DA … +2 more , Kedari KG, Paez PM
Front Cell Neurosci · 2026 · PMID 41778260 · Full text
Schwann cells (SCs), the myelin-forming glia of the peripheral nervous system (PNS), are essential for nerve development and maintenance; however, the contribution of Ca signaling to their maturation and long-term stabil...
Schwann cells (SCs), the myelin-forming glia of the peripheral nervous system (PNS), are essential for nerve development and maintenance; however, the contribution of Ca signaling to their maturation and long-term stability remains poorly understood. Here, we present a chemogenetic approach to selectively manipulate Gq-mediated Ca signaling in SCs across developmental stages. By combining -dependent expression of the excitatory DREADD hM3Dq with activation by clozapine-N-oxide, we achieved precise, temporally controlled stimulation of the canonical Gq-PLC-IP3-Ca cascade. , hM3Dq activation in immature SCs elevated basal Ca levels, amplified spontaneous oscillations, and suppressed voltage- and ligand-gated Ca influx, completely blocking SC maturation and myelin protein expression without affecting survival or proliferation. , early postnatal activation severely impaired sciatic nerve myelination, resulting in thinner myelin sheaths, fewer myelinated axons, and abnormal Remak bundle organization. Conversely, activation in mature SCs induced progressive demyelination, axonal degeneration, and motor deficits in adult mice. Ultrastructural and biochemical analyses confirmed widespread myelin loss and reduced expression of key myelin proteins, accompanied by increased g-ratios and axonal pathology. These findings uncover a previously unrecognized, bidirectional role for sustained Gq signaling in SC biology-blocking developmental myelination and destabilizing mature myelin through Ca dysregulation. Our study establishes excitatory DREADDs as a powerful tool for probing stage-specific signaling requirements in peripheral glia and highlights Ca homeostasis as a critical determinant of PNS integrity, with implications for demyelinating neuropathies and regenerative therapies.
Inflammatory mechanisms underlying early Alzheimer's disease pathology: evidence from the aging rhesus macaque brain.
Datta D, Wang M, Arnsten AFT
Front Cell Neurosci · 2026 · PMID 41767744 · Full text
Inflammation plays a large role in the etiology of the late onset, sporadic form of Alzheimer's disease (AD), yet these critical factors are not adequately modeled in mice where inflammatory mechanisms often differ widel...
Inflammation plays a large role in the etiology of the late onset, sporadic form of Alzheimer's disease (AD), yet these critical factors are not adequately modeled in mice where inflammatory mechanisms often differ widely from primates. In contrast, aging rhesus macaques offer a powerful translational model for investigating how advancing age and inflammation initiate early-stage pathology in sporadic AD, and for evaluating preventive therapeutic strategies. Unlike rodents, macaques possess highly developed association cortices with magnified calcium signaling, human-like inflammatory responses, and are naturally homozygous for ApoE-ε4-factors that together contribute to the spontaneous emergence of tau and amyloid pathology alongside cognitive decline. Critically, macaques allow the detection of early, soluble forms of hyperphosphorylated tau (pTau), including pT217Tau, which rapidly dephosphorylates postmortem and is rarely observable in human brain tissue outside of biopsies. New findings reveal that soluble pTau is neurotoxic and capable of propagating pathology across cortical networks, with elevated pT217Tau in plasma. Growing evidence points to age-related inflammatory signaling as a key driver of calcium dysregulation, which in turn promotes tau hyperphosphorylation, amyloid-β (Aβ) accumulation, synapse loss and autophagic degeneration. Both GCPII (glutamate carboxypeptidase II) and kynurenic acid inflammatory signaling have expanded roles in the primate association cortices that contribute to cognitive deficits. Pharmacological interventions in aged macaques demonstrate that targeting inflammation and restoring calcium homeostasis can significantly reduce pTau pathology with minimal side effects-highlighting a promising path for early intervention in AD.
C9orf72-ALS mutation drives basal mitophagy impairments in iNeurons.
Lee JAK, Moutin C, Granger S … +6 more , Roome K, Shaw A, Allen SP, Ferraiuolo L, Shaw PJ, Mortiboys H
Front Cell Neurosci · 2026 · PMID 41757350 · Full text
INTRODUCTION: ALS is a neurodegenerative disorder characterized by progressive upper and lower motor neuron loss. A GGGGCC hexanucleotide repeat expansion (HRE) in the C9orf72 gene is the most common mutation found in po...
INTRODUCTION: ALS is a neurodegenerative disorder characterized by progressive upper and lower motor neuron loss. A GGGGCC hexanucleotide repeat expansion (HRE) in the C9orf72 gene is the most common mutation found in populations of European descent. Mitochondrial dysfunction has been observed in C9orf72-ALS patients and models of the disease, however, reports on mitochondrial clearance via mitophagy in C9orf72-ALS are limited. RESULTS: iNeurons from C9orf72-ALS patients displayed reduced mitochondrial membrane potential and reduced basal mitophagy, due to reductions in autophagosome production and reduced ULK1 recruitment to mitochondria. No consistent changes to PINK1/Parkin or BNIP3 mitophagy pathways were observed. CONCLUSION: Our data show that certain aspects of mitochondrial function is impaired in C9orf72-ALS patient iNeurons. An in-depth characterization of mitophagy suggests that a deficit in autophagosome production is responsible and provides further evidence that toxic gain-of-function mechanisms in C9orf72-ALS are responsible for autophagy deficits.
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