Frontiers In Cellular Neuroscience[JOURNAL]
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200 papers
Adult organotypic brain slice cultures recapitulate extracellular matrix remodeling in hemorrhagic stroke.
Hewitt BJ, Roberts L, Roberts JA … +5 more , Fulton D, Hill LJ, Kitchen P, Bill RM, Botfield HF
Front Cell Neurosci · 2025 · PMID 41674548 · Full text
Haemorrhagic stroke is a devastating condition characterized by vessel rupture and free blood within the brain parenchyma or cerebrospinal fluid (CSF) filled spaces. Across the major subtypes of hemorrhagic stroke (subar...
Haemorrhagic stroke is a devastating condition characterized by vessel rupture and free blood within the brain parenchyma or cerebrospinal fluid (CSF) filled spaces. Across the major subtypes of hemorrhagic stroke (subarachnoid, intracerebral, and intraventricular hemorrhages), the presence of blood in the CSF generates significant tissue damage in the first 72 h after the event, known as early brain injury (EBI). EBI includes neuroinflammation, blood-brain barrier breakdown and dysregulation of extracellular matrix (ECM) dynamics. ECM dysfunction has been shown to trigger fibrosis of the cortical blood vessels, limiting normal CSF circulation and resulting in the buildup of metabolic waste or the development of post-hemorrhagic hydrocephalus. Limiting or preventing this fibrosis may therefore reduce the rate of morbidity experienced by survivors, providing a potential avenue for non-surgical treatment to reduce secondary brain injury post-stroke. Despite this, current approaches fail to differentiate between the effect of blood products and secondary consequences including intracranial pressure (ICP) elevation and mass effect. Here, we describe an adult rat organotypic brain slice culture (OBSC) model of hemorrhagic stroke which enables the identification of the effect of blood products on ECM dysregulation. We demonstrate the distribution of key cell types across a time course of 0, 3 and 7 days in culture, indicating that such cultures are viable for a minimum of 7 days. Using immunofluorescence staining, Western blotting and RNA sequencing, we show that exposure of OBSCs to lysed blood markedly increases ECM deposition around cortical blood vessels. This is accompanied by dysregulation of ECM regulatory genes and upregulation of inflammation and oxidative stress-related genes, successfully recapitulating the changes seen in human stroke survivors. This versatile model provides a translational platform to further understanding of hemorrhagic stroke pathophysiology and develop or trial novel therapeutics prior to progression to stroke studies.
Differential microglial dynamics and neuroinflammation underlying neuropathic pain in the central nervous system: comparative insights from spinal cord injury and compressive myelopathy models.
Kubota A, Nakajima H, Honjoh K … +3 more , Watanabe S, Takahashi A, Matsumine A
Front Cell Neurosci · 2026 · PMID 41660107 · Full text
INTRODUCTION: Neuropathic pain (NeP) is a major complication of spinal cord disorders that is refractory to therapy and impairs quality of life. Acute neuroinflammatory responses occur after spinal cord injury (SCI), but...
INTRODUCTION: Neuropathic pain (NeP) is a major complication of spinal cord disorders that is refractory to therapy and impairs quality of life. Acute neuroinflammatory responses occur after spinal cord injury (SCI), but chronic-phase microglia/macrophage (M/M) dynamics and their involvement in degenerative compressive myelopathy (DCM) are unclear. Brain M/M may contribute to persistent NeP; however, comparative analyses of SCI and DCM are lacking. The aim of this study was to investigate M/M activation and pain-related signaling dynamics in the spinal cord and brain, and their roles in chronic NeP following SCI and DCM. METHODS: Contusive SCI was induced in C57BL/6N mice. Chronic compression was modeled using / mice. Motor function was assessed using the Basso Mouse Locomotor Scale. Mechanical and thermal sensitivities were evaluated. M/M activation and pain-related molecules (p-p38, p-ERK1/2) were assessed in spinal and brain regions using immunohistochemical staining. Cytokine expression was analyzed using western blotting. RESULTS: SCI mice showed early M/M activation at the injured site with spread to the lumbar enlargement, paralleling mechanical and thermal hypersensitivity. In DCM, M/M activation increased with compression severity, but did not extend to the lumbar enlargement. Both models showed M/M and pain-related upregulation of molecules in the hippocampus and amygdala, and thalamic activation in acute SCI or moderate-to-severe compression. Pro-inflammatory cytokines peaked acutely in SCI and under moderate compression in DCM. Anti-inflammatory cytokine induction was limited in DCM. DISCUSSION: Distinct neuroinflammatory patterns underlie chronic NeP in SCI and DCM. SCI shows M/M activation shifting from the injured site to the lumbar enlargement and limbic brain regions, consistent with chronic below-level pain. DCM shows localized M/M activation, but earlier hippocampal/amygdalar involvement, consistent with chronic at-level pain. These findings suggest pathology-specific therapeutic windows for targeting M/M-mediated neuroinflammation to prevent NeP.
Extracellular vesicles in Niemann pick disease type C: current knowledge and future opportunities.
Hawthorne SCB, Sandau US, Saugstad JA
Front Cell Neurosci · 2025 · PMID 41658974 · Full text
Niemann Pick Disease Type C (NPC) is a rare neurodegenerative disease that primarily affects children. It is caused by mutations in the or genes, which encode proteins that transport cholesterol out of the endolysosoma...
Niemann Pick Disease Type C (NPC) is a rare neurodegenerative disease that primarily affects children. It is caused by mutations in the or genes, which encode proteins that transport cholesterol out of the endolysosomal organelles. Endolysosomal compartments also produce extracellular vesicles (EVs), which have emerged as key players in human disease. There is rapidly growing interest in how NPC cellular pathology impacts EV biology: of the 18 peer-reviewed publications on this topic, 13 were published within the last 5 years. Collectively, the existing literature suggests that the NPC proteins play key roles in EV biogenesis and uptake, that EV concentration and cargo are fundamentally altered in samples with NPC1/2 protein dysfunction, and that EVs may contribute to the therapeutic effects of NPC treatments. To better elucidate the connections between NPC and EVs further research is needed, especially in patient samples. Ultimately, a better understanding of the role of EVs in NPC will likely shed light on basic EV biology, related cellular neuropathologies, and a rare childhood disease that currently has no cure.
Glutamate load fosters spreading depolarization under osmotic stress in brain slices.
Frank R, Marinesco S, Bari F … +2 more , Menyhárt Á, Farkas E
Front Cell Neurosci · 2025 · PMID 41646256 · Full text
INTRODUCTION: Cerebral edema is a hallmark of lesion progression after acute ischemic stroke (AIS) and a major contributor to the evolution of spreading depolarizations (SDs). SDs trigger extracellular glutamate accumula...
INTRODUCTION: Cerebral edema is a hallmark of lesion progression after acute ischemic stroke (AIS) and a major contributor to the evolution of spreading depolarizations (SDs). SDs trigger extracellular glutamate accumulation and excitotoxic injury, yet the mechanisms linking edema formation, glutamate dysregulation, and SD dynamics remain incompletely understood. Here, we investigated how inhibiting glial swelling and volume-regulated glutamate release, or blocking neuronal ionotropic glutamate receptors alters SD features under hypo-osmotic stress in vitro. METHODS: Acute 350-µm-thick brain slices were prepared from male Wistar rats (n = 24). Edema was induced using hypoosmotic medium (130→60 mM NaCl), and SD was triggered by hypoxia. SD evolution and extracellular glutamate levels were monitored using local field potential recordings, intrinsic optical signal imaging, and enzyme-based glutamate biosensors. Astrocyte swelling was reduced by blocking AQP4+NKCC1 (TGN-020 + bumetanide) and VRAC channels (DCPIB), while neuronal NMDA and AMPA/kainate receptors were antagonized with MK-801 + CNQX. RESULTS: Inhibition of AQP4, NKCC1, or VRAC channels restricted the cortical area invaded by SD, shortened SD duration, and reduced extracellular glutamate accumulation. In contrast, blockade of NMDA or AMPA/kainate receptors markedly decreased SD propagation and glutamate buildup. Both astrocytic and neuronal interventions disrupted typical SD initiation patterns, producing atypical, multifocal SD events. DISCUSSION: These findings demonstrate that astrocyte volume regulation and neuronal ionotropic glutamate receptors jointly shape SD characteristics under osmotic stress, identifying astrocytic water/ion homeostasis and glutamatergic signaling as potential therapeutic targets to limit excitotoxic injury in acute cerebrovascular disease.
The potential mechanisms and regulatory roles of exosomal miRNA in neural repair after spinal cord injury.
Shi Y, Li Z, Pu Y … +4 more , Wang Q, Cui Z, Qi L, Sun Y
Front Cell Neurosci · 2025 · PMID 41641015 · Full text
Spinal cord injury (SCI) is a devastating disorder of the central nervous system. It is characterized by primary mechanical damage and secondary pathological cascades. These lead to persistent sensory and motor deficits,...
Spinal cord injury (SCI) is a devastating disorder of the central nervous system. It is characterized by primary mechanical damage and secondary pathological cascades. These lead to persistent sensory and motor deficits, substantial socioeconomic burdens, and limited therapeutic efficacy. Exosomes are nanoscale vesicles secreted by various cells that serve as key mediators of intercellular communication by delivering bioactive molecules, particularly microRNAs (miRNAs), which regulate gene expression in target cells. This review explores how exosomal miRNAs contribute to neural repair in SCI. These contributions include inhibiting neuroinflammation via pathways such as NF-κB and TLR4; suppressing neuronal apoptosis through PTEN/PI3K/Akt signaling; promoting axonal regeneration via the ERK1/2/STAT3 and NGF/TrkA pathways, enhancing angiogenesis by targeting SPRED1 and integrin α5, and modulating of the immune microenvironment toward M2 polarization, and multifaceted neuroprotection involving alleviating autophagy and endoplasmic reticulum stress. Drawing on recent preclinical studies from 2024-2025, including those utilizing mesenchymal stem cell-derived exosomes loaded with miRNAs such as miR-124-3p, miR-338-5p, and miR-216a-5p, the review highlights promising innovations, such as bioengineered exosomes and biomaterial integrations. Recent preclinical advancements, such as exosome-based therapies that have shown reduced lesion volumes and improved motor function in rodent models, highlight the potential for translation to clinical applications. Ongoing efforts are anticipated to lead to clinical trials in the near future. Despite challenges in standardization, delivery efficiency, immunogenicity, and long-term safety, exosomal miRNA therapy offers a cell-free, multitargeted approach with strong potential for clinical translation in SCI management.
Intermittent fasting reduces glaucomatous damage in an HSP27 autoimmune mouse model.
Maler DL, Reinehr S, Deppe L … +2 more , Dick HB, Joachim SC
Front Cell Neurosci · 2025 · PMID 41641014 · Full text
BACKGROUND: Currently, the treatment of glaucoma is limited to reducing intraocular pressure since other involved pathomechanisms are not well understood yet. Evidence points to an immune-mediated component in disease de...
BACKGROUND: Currently, the treatment of glaucoma is limited to reducing intraocular pressure since other involved pathomechanisms are not well understood yet. Evidence points to an immune-mediated component in disease development. For example, elevated antibody levels against heat shock protein 27 (HSP27) were detected in glaucoma patients. In mice, we previously noted glaucoma-like damage after an intravitreal HSP27 injection. Now, we aimed to investigate if intermittent fasting protects from this glaucomatous damage. METHODS: CD1 mice were intravitreally injected with HSP27 into one eye. The contralateral eye served as a control. After injections, half of the animals received food ad libitum (no diet). The other half fasted, hence access to food was denied for 24 h at three days per week (diet). The animals were weighed weekly. Retinal thickness was analyzed via optical coherence tomography (OCT) after 4 weeks ( = 7 eyes/group). Via immunohistology, retinal ganglion cells (RGCs), apoptotic cells, macroglia, microglia/macrophages, tumor necrosis factor (TNFα), and interleukin (IL)-1β were analyzed ( = 6 eyes/group). Corresponding markers were examined with RT-qPCR ( = 4 samples/group). In addition, microarray assays were performed from serum samples from mice with diet or with no diet ( = 6 samples/group). RESULTS: The weight and OCT measurements revealed no differences between the groups. HSP27 retinas had significantly lower RGC numbers as well as decreased mRNA levels compared to controls, while HSP27+diet retinas displayed similar RGC counts as controls. No difference was observed in apoptotic markers. The macroglia area was increased in HSP27 tissue, while the HSP27+diet group showed no difference to controls. The number of microglia was not altered after HSP27 injection but was lower in HSP27+diet retinas. and expression levels were downregulated in HSP27+diet samples compared to control as well as HSP27 tissue. Moreover, different pro-inflammatory cytokines, including IL-1β and IL-6, were lower in the serum of diet mice compared to no diet ones. CONCLUSION: Intravitreal injection of HSP27 resulted in RGC loss and was associated with gliosis. In contrast, intermittent fasting conferred neuroprotective effects, likely by modulating neuroinflammatory pathways, and hence protected RGCs from damage. These findings highlight intermittent fasting as a potential adjunctive therapeutic strategy for glaucoma management.
Early transcriptomic perturbations highlight the spinal cord as a key pathogenic region in spinocerebellar ataxia type 3.
Emerson J, Nelthrope BS, Walker EA … +3 more , Mao G, Shorrock HK, McLoughlin HS
Front Cell Neurosci · 2025 · PMID 41613623 · Full text
Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease caused by polyglutamine repeat expansion in the gene. Despite the ubiquitous expression of ATXN3 throughout the body, SCA3 pathology is most pronounced...
Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease caused by polyglutamine repeat expansion in the gene. Despite the ubiquitous expression of ATXN3 throughout the body, SCA3 pathology is most pronounced in select, vulnerable central nervous system regions. Notably, spinal cord atrophy that is detectable by MRI emerges prior to ataxia symptom onset and progresses with disease severity. However, the pathogenic molecular signatures of the SCA3 spinal cord remain largely unexplored. Here, we present the first comprehensive analysis of the spinal cord transcriptome in SCA3 using both human and mouse model tissue. Our data reveal both early and progressive transcriptional dysregulation in the spinal cord, impacting key biological processes such as lipid metabolism, inflammation, cellular structure, and nucleic acid processing. Transcriptomic profiling of knockout mouse spinal cord revealed only subtle transcriptional changes with little overlap to those in SCA3 knock-in mice, indicating that spinal cord pathology arising from gene expression changes are due to mutant ATXN3 toxic gain-of-function mechanisms, rather than ATXN3 loss-of-function. In addition, we observed aberrant RNA splicing changes in KI mice, particularly in oligodendrocyte signature genes. Collectively, these novel findings position the spinal cord as a primary and early site of SCA3 pathogenesis and underscore its potential both as a sensitive regional biomarker for disease progression and as a key target for therapeutic intervention.
Non-hematopoietic erythropoietin splice variant is produced in the diseased human brain and confers neuroprotection.
Hartung T, Freyer D, Zemella A … +5 more , Radbruch H, Weiner J, El-Din JJ, Meisel A, Priller J
Front Cell Neurosci · 2025 · PMID 41602576 · Full text
Erythropoietin (EPO) is a pleiotropic cytokine with important functions in neuronal development and neuroprotection, but hematopoietic effects limit the therapeutic application of EPO in neurological diseases. We discove...
Erythropoietin (EPO) is a pleiotropic cytokine with important functions in neuronal development and neuroprotection, but hematopoietic effects limit the therapeutic application of EPO in neurological diseases. We discovered human endogenous EPO splice variants that are non-hematopoietic but cytoprotective. Here, we demonstrate at the single-cell level that an alternative splice variant lacking exon 3 (hS3) is expressed in the human brain and is upregulated above EPO mRNA levels in ischemic and inflammatory neurological diseases. Conversely, hS3 mRNA expression is reduced below EPO levels in neurodegenerative disease. In an oxygen-glucose deprivation (OGD) model of ischemia, a single dose of cell-free synthesized constant glycosylated active hS3 protects neuronal cultures derived from human induced pluripotent stem cells (hiPSC) and human embryonic stem cells (hESC) more effectively than EPO. We identify the D-helix as a key functional domain of hS3 and demonstrate that the neuroprotective effect is enhanced by PD29, a novel small peptide derived from the D-helix of hS3. Long-term hS3 administration increases the neuroprotective effects in the OGD model by dose-dependent differential expression of apoptosis-related protein-coding genes and long non-coding RNAs (lncRNAs). In addition, our results suggest that hS3 induces early cell cycle inhibition without impairing differentiation of hiPSC and hESC into neuronal subtypes. In conclusion, EPO splice variant hS3 is part of the endogenous neuroprotective system in the human brain with significant therapeutic potential.
Modulation of axon excitable domains by astrocytes and microglia.
Garrido JJ
Front Cell Neurosci · 2025 · PMID 41585446 · Full text
Neuronal communication depends on neuronal polarity and the integrity of axonal excitable domains, including the axon initial segment (AIS), nodes of Ranvier, and presynaptic terminals. In addition to the influence of ne...
Neuronal communication depends on neuronal polarity and the integrity of axonal excitable domains, including the axon initial segment (AIS), nodes of Ranvier, and presynaptic terminals. In addition to the influence of neuronal input on their function and plasticity, recent evidence suggests that glial cells play a significant role in regulating these domains under both physiological and pathological conditions. In this context, this review focusses on the roles of astrocytes and microglia in the physiological modulation of the AIS and nodes of Ranvier and how these glial cells are involved in several pathological contexts, beyond its participation in the tripartite synapse. The AIS and nodes of Ranvier are not only essential for the initiation and propagation of neuronal signals but also serve as key sites of interaction with astrocytes and microglia. These interactions are crucial for maintaining neuronal excitability and overall neural circuit health. Disruptions in the interactions between glial cells and the AIS or nodes of Ranvier-whether caused by injury or disease-can profoundly affect central nervous system (CNS) function, emphasizing the importance of this dynamic relationship in both normal and pathological contexts. Recent studies have highlighted the roles of astrocytes and microglia in contacting the AIS and nodes of Ranvier, contributing to their structural plasticity, as well as in maintaining their homeostasis through the secretion of signaling factors and the regulation of ion concentrations in their microenvironment. However, the mechanisms underlying these regulatory processes remain largely unknown, and further research is required to elucidate how these interactions influence axonal physiology and contribute to axonal pathology.
Editorial: Celebrating the year of Ramon y Cajal: cellular biology of the retina.
Cuenca N, Canto-Soler MV, Becerra SP
Front Cell Neurosci · 2025 · PMID 41568287 · Full text
Abstract loading — click title to view on PubMed.
Hot topics in Cellular Neuropathology IV-targeting neurological diseases by gene therapy approaches.
Hermann DM
Front Cell Neurosci · 2025 · PMID 41568286 · Full text
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Correction: Advances in astrocytic calcium signaling research.
Chen Y, Ye Y, Jia J … +3 more , Long B, Dou T, Yan X
Front Cell Neurosci · 2025 · PMID 41561770 · Full text
[This corrects the article DOI: 10.3389/fncel.2025.1719532.].
[This corrects the article DOI: 10.3389/fncel.2025.1719532.].
Trazodone modulates behavioral alterations in scopolamine-induced cognitive deficit by targeting brain-derived neurotropic factor and cAMP response element-binding protein signaling.
Dhaka P, Pinky, Neha … +4 more , Khan MA, Rabbani SA, El-Tanani M, Parvez S
Front Cell Neurosci · 2025 · PMID 41550299 · Full text
BACKGROUND: Trazodone, an antidepressant, may play a potential role in enhancing long-term memory by combining anxious behavior deficits induced by scopolamine. The current study proposes the potential novel mechanistic...
BACKGROUND: Trazodone, an antidepressant, may play a potential role in enhancing long-term memory by combining anxious behavior deficits induced by scopolamine. The current study proposes the potential novel mechanistic insights between oxidative stress and memory biomarkers, including BNDF and CREB pathways, to modulate the pathogenesis of AD-like symptoms. METHODS: Behavioral deficits were studied in terms of biochemical determination of lipid peroxidation and acetylcholinesterase activities. In addition, the study looked at the immunohistochemistry of BDNF and CREB against scopolamine-induced AD-like symptoms. Moreover, histopathological alterations were also performed against an AD-like model. Aβ proteins immunofluorescence was performed due to its known mechanism under AD. Finally, scopolamine-induced intraperitoneal mechanisms were studied in rats to establish an AD-like model. RESULTS: The present study findings showed that administration of TRAZ considerably improved cognitive impairments as validated by NOR and display of anti-anxiety behavior, as verified by EPM. In addition, biochemical findings confirmed that TRAZ lowered oxidative stress through LPO, reduced Aβ deposition, and decreased the AChE. Furthermore, there was a notable upregulation of BDNF and CREB signaling expression, as confirmed by the IHC. CONCLUSION: Overall, the study findings confirmed that TRAZ could be useful in mitigating the negative effects of scopolamine-induced cognitive impairment and lowering oxidative stress by enhancing memory indicators.
Unmasking early microglial remodeling in an Alzheimer's disease mouse model.
Saminathan P, McArdle S, Corey M … +5 more , Nadig N, Fang C, Gibbons A, Rayadurgam M, Sharma S
Front Cell Neurosci · 2025 · PMID 41550298 · Full text
Early neuroimmune remodeling is a critical yet understudied component of Alzheimer's disease (AD) pathogenesis. To investigate microglial contributions to AD development prior to overt plaque deposition, we developed an...
Early neuroimmune remodeling is a critical yet understudied component of Alzheimer's disease (AD) pathogenesis. To investigate microglial contributions to AD development prior to overt plaque deposition, we developed an open-source morphometric pipeline to systematically quantify hippocampal microglial structure and activation states in pre-plaque 5xFAD mice. Across ∼11,000 cells, we extracted multidimensional parameters including area, circularity, convex hull, branch points, nearest-neighbor distance, and nuclear features, alongside Iba1 and CD68 intensity measurements. While no significant overt gliosis was observed at this early stage, microglia from 5xFAD mice exhibited subtle trends toward increased structural complexity compared to wild-type controls. Importantly, significant sex-specific differences were detected within the CA1 subregion: male 5xFAD microglia displayed hyper-ramified morphologies consistent with enhanced surveillance states, whereas female microglia demonstrated greater density and a more reactive phenotype. Correlation analyses revealed a conserved association between microglial complexity and Iba1/CD68 expression, independent of sex or genotype, underscoring a fundamental link between cytoskeletal remodeling and phagolysosomal activity. These findings highlight the capacity of morphometric profiling to sensitively detect early, region-specific, and sex-dependent shifts in microglial phenotype before amyloid deposition. By integrating quantitative morphology with canonical molecular markers, this framework provides a robust and unbiased approach for characterizing microglial activation trajectories. Such early readouts may inform biomarker discovery and therapeutic strategies aimed at modulating microglial responses to delay or prevent AD progression.
Galectin-3 shapes microglial phenotype through endogenous and exogenous mechanisms.
Camprubí-Ferrer L, Yang Y, Fernández-Calle R … +4 more , Boza-Serrano A, García-Revilla J, Frontiñán-Rubio J, Deierborg T
Front Cell Neurosci · 2025 · PMID 41487996 · Full text
Galectin-3 (Gal3) is a multifunctional lectin expressed and released by microglia, where it influences diverse processes in both homeostasis and disease. To dissect its intracellular and extracellular roles, we generated...
Galectin-3 (Gal3) is a multifunctional lectin expressed and released by microglia, where it influences diverse processes in both homeostasis and disease. To dissect its intracellular and extracellular roles, we generated Gal3-deficient BV2 microglial cells and systematically assessed how genetic deletion and exogenously added recombinant Gal3 shape microglial physiology. Gal3 deletion increased cell area, mitochondrial activity, and motility without affecting proliferation, linking endogenous Gal3 to microglial energetic control and dynamic cellular physiology. Endogenous Gal3 was required to maintain CD11b surface levels, and restrains TREM2 and Clec7a expression, whereas exogenous Gal3 promoted CD45 internalization and drove a paracrine TNFα release. Endogenous and exogenous Gal3 are synergistically needed for Syk phosphorylation and NOX2 expression. Internalization assays demonstrated that endogenous Gal3 constrained phagocytosis and endocytosis, while exogenous Gal3 enhanced endocytosis in a paracrine manner. In the Alzheimer's disease 5xFAD mouse model, where Gal3 deletion was reported to lower amyloid plaque burden, the absence of Gal3 does not affect microgliosis but elevates Clec7a levels around plaques. Together, these findings reveal Gal3 as a critical regulator of microglial homeostasis, uptake pathways, receptor expression, and inflammatory signaling. We have defined a novel microglial regulation based on endogenous and exogenous pools of Gal3. By identifying a novel Gal3-Clec7a interaction, this work highlights Gal3 as a key modulator of microglial phenotype and a potential target for therapeutic modulation of neuroinflammation.
Parvalbumin interneurons: the dark and bright sides of a key playmaker of neural circuits and behavior.
Wirk E, Quairiaux C, Marissal T
Front Cell Neurosci · 2025 · PMID 41487995 · Full text
With their morphological and electrophysiological properties as well as exceptional connectivity, parvalbumin interneurons play a major role in the dynamics of the neural circuits of the hippocampus and cortex, along wit...
With their morphological and electrophysiological properties as well as exceptional connectivity, parvalbumin interneurons play a major role in the dynamics of the neural circuits of the hippocampus and cortex, along with associated cognitive functions. Their dysfunction, which is sometimes reversible, contributes to significant disruptions in network activity and behavioral deficits related to various diseases such as epilepsies or neuropsychiatric disorders. In this Mini Review, we present these parvalbumin interneurons, their characteristics, pathophysiological roles, and propose avenues for future investigations.
Architecture and cellular composition of focal cortical dysplasia type II: qualitative review of histological studies.
Castaño-Martín R, Metais A, Ciura S … +1 more , Blauwblomme T
Front Cell Neurosci · 2025 · PMID 41487994 · Full text
Focal cortical dysplasia (FCD) is a malformation of cortical development strongly associated with drug-resistant epilepsy, particularly in children but also observed in adults. FCD type II is specifically characterised b...
Focal cortical dysplasia (FCD) is a malformation of cortical development strongly associated with drug-resistant epilepsy, particularly in children but also observed in adults. FCD type II is specifically characterised by cortical disorganisation and the presence of abnormal cells. This condition has been widely linked to hyperactivation of the mTOR signalling pathway, secondary to somatic mutations. After five decades of research, the comprehensive understanding of FCD architecture remains incomplete, with significant variability across studies, influenced by differences in tissue samples, cohort characteristics, and experimental protocols. This review aims to synthesise current knowledge on FCD architecture to clarify how the cerebral cortex is altered in FCD. We particularly focus on the hallmarks of FCD: cortical dislamination, balloon cells, and dysmorphic neurons. Additionally, we explore recent insights into the composition of cortical neuronal populations, emphasising the role of inhibitory interneuron populations, which have gained attention following discoveries regarding the involvement of GABAergic signalling in epileptogenesis. Overall, our review highlights key considerations for future single-cell and spatial studies aimed at minimising sampling bias.
Age dependent seizure susceptibility of CA2 hippocampal neurons.
Correa J, Sablani S, Wasfi M … +2 more , Correa C, Bandelow S
Front Cell Neurosci · 2025 · PMID 41480494 · Full text
The hippocampal CA2 region is increasingly recognized as a functionally distinct subfield essential for social recognition memory and the proper routing of information through the hippocampal circuit. Unlike the CA1 and...
The hippocampal CA2 region is increasingly recognized as a functionally distinct subfield essential for social recognition memory and the proper routing of information through the hippocampal circuit. Unlike the CA1 and CA3 subfields, CA2 pyramidal neurons show relative sparing from seizure-associated cell loss in many adult models of epilepsy; however, this resilience is not absolute, as recent work demonstrates that CA2 can also exhibit heightened excitability and contribute to seizure propagation under certain models and pathological conditions. Multiple cellular and molecular features-including dense inhibitory interneuron networks, enriched expression of RGS14, PCP4, STEP, perineuronal nets (PNNs), and specialized calcium-handling machinery-collectively constrain synaptic plasticity and reduce excitotoxic vulnerability in mature CA2 neurons. In contrast, these protective mechanisms are underdeveloped during early postnatal periods, rendering the CA2 region more susceptible to hyperexcitation and circuit disruption. Early-life seizures (ELS) occurring within this developmental window may therefore adversely reshape CA2 connectivity and function, potentially altering social memory formation and contributing to later-life cognitive or behavioral impairments. Understanding how CA2 transitions from early vulnerability to adult resilience provides a critical framework for linking developmental epileptogenic insults to long-term deficits in social and mnemonic processing.
Neural stem cells fate under neuroinflammatory conditions and oxidative stress response.
Torrisi F, Denaro S, Ragonese J … +3 more , D'Aprile S, Zappalà A, Parenti R
Front Cell Neurosci · 2025 · PMID 41480493 · Full text
Neural stem cells (NSCs) are defined by their self-renewal capacity and multipotent differentiation potential, making them essential for nervous system development and for the maintenance of adult brain homeostasis. Alth...
Neural stem cells (NSCs) are defined by their self-renewal capacity and multipotent differentiation potential, making them essential for nervous system development and for the maintenance of adult brain homeostasis. Although confined to the subventricular zone and the subgranular zone of the hippocampus in adulthood, NSCs preserve a functional capacity for neurogenesis and tissue regeneration. This regenerative potential becomes particularly important in neuropathological conditions, where tissue damage is often accompanied by neuroinflammation and oxidative stress. Within this hostile microenvironment, NSCs have to cope with inflammatory mediators and reactive oxygen species that can affect their survival, proliferation, and cellular differentiation. NSCs also are actively modulated by diverse molecular pathways in response to stress conditions promoting stemness or stem cell exhaustion. Therefore, understanding the crosstalk between neuroinflammatory and oxidative stress in NSCs fate is crucial for elucidating the mechanisms of neurogenesis and homeostasis recovery and for designing therapeutic strategies.
Mitochondrial and ER stress crosstalk in TBI: mechanistic insights and therapeutic opportunities.
Wenzhe L, Boyang X, Yuchao G … +2 more , Bimcle R, Yue Y
Front Cell Neurosci · 2025 · PMID 41480492 · Full text
Traumatic brain injury (TBI) remains a major global public health concern, characterized by high morbidity, mortality, and long-term disability. Beyond the primary mechanical insult, the progression of secondary injuries...
Traumatic brain injury (TBI) remains a major global public health concern, characterized by high morbidity, mortality, and long-term disability. Beyond the primary mechanical insult, the progression of secondary injuries-including neuroinflammation, oxidative stress, mitochondrial dysfunction, and excitotoxicity-plays a decisive role in long-term neurological outcomes. Emerging evidence positions cellular stress responses at the core of TBI pathophysiology, mediating the transition from acute injury to chronic neurodegeneration. This review systematically outlines the major stress phenotypes triggered by TBI, including oxidative stress, endoplasmic reticulum (ER) stress, mitochondrial distress, and autophagy imbalance. Particular emphasis is placed on the molecular interplay between the mitochondria and ER, where the mitochondria-associated membranes (MAMs) serve as dynamic hubs regulating calcium (Ca) homeostasis, ATP production, and apoptotic signaling. Disruptions in Ca flux through MAMs exacerbate energy failure and promote reactive oxygen species (ROS) overproduction, triggering pro-inflammatory cascades and neuronal apoptosis. Furthermore, the crosstalk between ER-mitochondrial stress integrates signals that govern autophagy and inflammatory responses via key nodes such as C/EBP Homologous Protein (CHOP), Nuclear factor erythroid 2-related factor 2(Nrf2), and Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB). We also explore how stress crosstalk mechanistically contributes to neurological dysfunctions, including glial activation, axonal injury, and progressive cognitive-behavioral impairments. Understanding these intricate molecular mechanisms not only elucidates the pathogenesis of secondary brain damage but also unveils novel therapeutic targets for intervention. Targeting stress response integration may represent a transformative approach in preventing long-term disability and enhancing neuroregenerative outcomes following TBI.
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