Frontiers In Cellular Neuroscience[JOURNAL]
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200 papers
Neurovascular unit remodeling: focusing on glial cells in stroke injury and recovery.
Gong M, Li X, Yuan Q … +6 more , Pang L, Ye X, Li S, Li Y, Guo H, Jin S
Front Cell Neurosci · 2026 · PMID 42222057 · Full text
Stroke stands as a predominant global contributor to mortality and persistent disability, marked by a sequential cascade of pathophysiological perturbations. Moving beyond the traditional neuron-focused paradigm, contemp...
Stroke stands as a predominant global contributor to mortality and persistent disability, marked by a sequential cascade of pathophysiological perturbations. Moving beyond the traditional neuron-focused paradigm, contemporary stroke research has increasingly centered on the neurovascular unit (NVU), a functional multicellular assembly encompassing neurons, glial cells, and cerebrovascular components, as the pivotal regulatory hub for cerebral homeostasis and adaptive responses to injury. Among NVU components, glial cells are no longer viewed as passive supporters but as active regulators of NVU integrity, blood-brain barrier (BBB) functionality, immune surveillance, and tissue repair processes. Stroke trigger distinct spatiotemporal phenotypic changes in glial cells. Microglia show biphasic pro-inflammatory and pro-repair polarization. Astrocytes undergo reactive gliosis and form glial scars with dual functions. Oligodendrocytes experience iron-related or ischemic injury and contribute to remyelination. Hypertension, hyperglycemia and aging jointly induce glial dysfunction and predispose the NVU to a pre-vulnerable state that worsens post-stroke damage. This review emphasizes the multifaceted roles of glia-mediated NVU remodeling in stroke injury and recovery, addresses the modulatory effects of comorbid risk factors on glial functions and explores glia-targeted therapeutic strategies that hold promise for preserving NVU function and improving stroke outcomes.
Perinatal mAChR-mediated activation of cortical subplate neurons elicits network activity driving basket cell differentiation.
Wahle P, Kaczmarski M, Riedel C … +9 more , Hamad MIK, Arne O, Dupont E, Jack A, Rennau LM, Räk A, Luhmann HJ, Köhler I, Patz S
Front Cell Neurosci · 2026 · PMID 42222056 · Full text
The activation of mAChR on subplate neurons has been shown to trigger oscillatory glutamatergic network activity in early postnatal neocortex. Here, we explored the long-term consequences of subplate activation on the di...
The activation of mAChR on subplate neurons has been shown to trigger oscillatory glutamatergic network activity in early postnatal neocortex. Here, we explored the long-term consequences of subplate activation on the differentiation of cortical neurons. Stimulating newborn somatosensory and visual cortex ex vivo and organotypic cortex cultures (OTCs) of the visual cortex with carbachol (CCH) led to an upregulation of and . In OTCs, the stimulation increased the amplitude and frequency of calcium events in the gray matter layers at DIV 3-5. At DIV 5, an acute stimulation rapidly activates p21ras; increases ERK phosphorylation; induces and expression; and increases GluN1, GluN2A, GluN2B, PSD-95, GAD-65, and synaptophysin protein expression. The NMDA receptors were functional, as shown by enhanced ligand-induced dendritic injury. Repeated DIV 1-5 mAChR activation increased, at DIV 10, the expression of GluN2A, of an essential protein of the inhibitory presynapse, VGAT, and the basket-cell-specific presynaptic calcium sensor synaptotagmin-2. Furthermore, it increased the frequency of interneuronal calcium events at DIV 10-15, dendritic length of basket cells, and accelerated the local arborization of basket cell axons at DIV 15. The results suggest that temporally limited mAChR-mediated activation of subplate neurons evokes glutamatergic network activity, which, gradually over the following weeks, promotes cortical circuit development. Specifically, it enhances the expression of excitatory and inhibitory synaptic proteins and accelerates the morphological and functional maturation of basket cells, highlighting the cholinergic input to subplate neurons as a critical regulator of interneuron development.
The bradykinin B2 receptor as a context-dependent modulator of neural circuit function.
Silva JLS, Tavares MR, Lavezo L … +1 more , Wasinski F
Front Cell Neurosci · 2026 · PMID 42211761 · Full text
The kallikrein-kinin system (KKS) is a proteolytic signaling pathway traditionally associated with vascular regulation and inflammation, but increasing evidence indicates that its components are also expressed in the cen...
The kallikrein-kinin system (KKS) is a proteolytic signaling pathway traditionally associated with vascular regulation and inflammation, but increasing evidence indicates that its components are also expressed in the central nervous system. The bradykinin B2 receptor (B2R), the main mediator of kinin signaling, has been implicated in neuronal differentiation, synaptic modulation, and activity-dependent neuroplasticity. However, its physiological role in neural circuit regulation remains poorly understood. Recent studies using cell-type-specific genetic models suggest that neuronal B2R signaling is largely dispensable for maintaining basal behavioral states. In contrast, growing evidence indicates that B2R plays a more prominent role in glial-mediated inflammatory responses, particularly in astrocytes. Here, we propose that B2R functions as a context-dependent neuromodulatory system that links neuroinflammatory signaling to neural circuit plasticity. Within this framework, B2R activation may become functionally relevant during inflammatory conditions or physiological stimulation, influencing dopaminergic circuits involved in motivation and reward-related behaviors.
Prenatal stress shapes discrete responses during early recovery from repeated adult stress.
Verosky BG, Anderson JL, Chen HJ … +3 more , Rajasekera TA, Yang F, Gur TL
Front Cell Neurosci · 2026 · PMID 42211760 · Full text
INTRODUCTION: Prenatal stress is associated with increased risk for psychiatric disorders in offspring, yet many exposed individuals do not develop psychopathology, suggesting prenatal stress may confer a latent vulnerab...
INTRODUCTION: Prenatal stress is associated with increased risk for psychiatric disorders in offspring, yet many exposed individuals do not develop psychopathology, suggesting prenatal stress may confer a latent vulnerability that emerges only under later-life challenge. We have previously demonstrated long term neuroinflammation and behavioral changes following exposure to prenatal stress, but had not examined whether the offspring were vulnerable to adult stressors, which is translationally relevant. METHODS: To test whether prenatal stress alters the stress response and stress recovery following repeated stress, pregnant dams underwent prenatal restraint stress (GD10.5-GD16.5), and adult offspring of both sexes were assigned to a 1-week adult restraint regimen or adult control in a 2 × 2 factorial design. Anxiety-like and social behavior was assessed after the stress paradigm in adulthood, and endocrine and transcriptional endpoints were measured immediately after stress and during early recovery. RESULTS: Repeated adult restraint elicited a robust but transient corticosterone response and induced broad, largely time-limited stress-responsive transcription across prefrontal cortex, hippocampus, amygdala, and hypothalamus. Prenatal stress did not globally potentiate HPA-axis output or canonical glucocorticoid-responsive gene induction under this strong adult stressor, but instead produced selective, context-dependent effects on stress- related behavior and region- and sex-specific gene regulation during the acute and recovery phases. DISCUSSION: Collectively, the data indicate that under a strong repeated adult stressor, prenatal stress is associated with selective differences in the pattern and timing of behavioral and transcriptional responses across stress-regulatory circuitry, rather than a uniform modulation in HPA-axis output. This pattern underscores a complex, long-term interplay between prenatal stress exposures and later-life stressors, which together may shape vulnerability or resilience to adult psychopathology.
Editorial: Retinitis pigmentosa, macular degeneration and related diseases.
Weiss ER, Han Z
Front Cell Neurosci · 2026 · PMID 42179847 · Full text
Abstract loading — click title to view on PubMed.
Clozapine-N-oxide impairs spatial memory independent of DREADDs.
Bunce B, VanKampen AA, He A … +2 more , Aton SJ, Raven F
Front Cell Neurosci · 2026 · PMID 42179846 · Full text
Chemogenetic studies using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) enable the precise manipulation of neuronal activity in specific brain regions and cell types. DREADDs are widely used to di...
Chemogenetic studies using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) enable the precise manipulation of neuronal activity in specific brain regions and cell types. DREADDs are widely used to dissect neural circuits underlying animal behavior, including learning and memory. Clozapine-N-Oxide (CNO), a metabolite of clozapine and one of the earliest-developed ligands for muscarinic DREADDs, was initially considered pharmacologically inert. However, CNO is now known to undergo back-metabolism to clozapine, leading to undesired off-target behavioral effects, including alterations in locomotion and anxiety-related behaviors. New ligands such as Compound 21 (C21) have been developed to improve selectivity and reduce these effects. However, despite their widespread use, no studies to date have directly compared the effects of CNO and C21 themselves on specific cognitive processes such as hippocampus-dependent memory formation. Here, we measured acute effects of CNO and C21 on spatial memory encoding, using an object-location memory (OLM) paradigm in male and female mice. We also quantified encoding-associated hippocampal principal neuron and parvalbumin (PV) interneuron activity by measuring cFos expression in these populations. Across dorsal hippocampal subregions, neither ligand altered overall neuronal activity nor PV interneuron activity during encoding. Nonetheless, we find that CNO administration impairs OLM encoding, while C21 does not. Together, these findings highlight a previously unrecognized behavioral effect of CNO administration on hippocampus-dependent memory formation-even in the absence of DREADD expression-and indicate that C21 may be a preferable ligand for chemogenetic studies examining memory and hippocampal function.
Mesenchymal stromal/stem cell-derived extracellular vesicles in brain disorders: mechanisms of repair and recovery.
Nakazaki M, Lankford KL, Ukai R … +5 more , Hirota R, Oka S, Sasaki M, Kocsis JD, Honmou O
Front Cell Neurosci · 2026 · PMID 42179845 · Full text
Mesenchymal stem/stromal cell-derived small extracellular vesicles (MSC-sEVs) have emerged as promising cell-free therapeutics for central nervous system (CNS) disorders including stroke, traumatic brain injury (TBI), de...
Mesenchymal stem/stromal cell-derived small extracellular vesicles (MSC-sEVs) have emerged as promising cell-free therapeutics for central nervous system (CNS) disorders including stroke, traumatic brain injury (TBI), dementia, and multiple sclerosis (MS). MSC-sEVs offer advantages of low immunogenicity, ease of storage, and ability to cross the blood-brain barrier. This review provides a comprehensive analysis of the mechanisms by which MSC-sEVs have been reported to promote neural repair and recovery in preclinical models, through two convergent categories of action. First, MSC-sEVs exert direct neurorestorative effects, including activation of endogenous neural stem cells via Wnt/beta-catenin and PI3K/Akt/mTOR signaling, neuroprotection through PTEN/Akt-mediated anti-apoptotic and antioxidant pathways, preservation of mitochondrial function through mitophagy regulation, and promotion of neurite outgrowth and synaptogenesis through cytoskeletal remodeling and growth signaling. Second, MSC-sEVs modulate the injury microenvironment by shifting microglia and infiltrating macrophages toward anti-inflammatory phenotypes through NF-kB pathway modulation, converting reactive astrocytes to neuroprotective states, promoting angiogenesis and blood-brain barrier restoration, and enhancing oligodendrogenesis and remyelination. These effects are mediated largely through the transfer of microRNAs and other bioactive cargo to target cells at the injury site, although the relative contribution of individual cargo components remains to be fully established. We discuss how these actions address the pathophysiology of stroke, Alzheimer's disease, vascular dementia, TBI, and MS, highlighting disease-specific mechanisms and the current gap between preclinical evidence and clinical validation. Finally, we address challenges for clinical translation, including standardization of critical quality attributes and potency assays, route-dependent biodistribution, safety considerations, and dosing optimization. We also discuss engineering strategies for enhanced efficacy, including surface modification for CNS-targeted delivery, source cell preconditioning, cargo engineering, and scaffold-based sustained release systems. Although no clinical trials have yet evaluated MSC-sEV therapy specifically for neurological disorders, the growing body of safety data from non-neurological MSC-sEV trials and the extensive clinical experience with parent MSC therapies provide a foundation for future CNS-focused studies. MSC-sEVs hold substantial potential as a cell-free approach for neurological disorders that currently lack effective regenerative therapies, although realization of this potential will require rigorous clinical validation.
Morphological details contribute to neuronal response variability within the same cell type.
Sandbote K, Arkhypchuk I, Kretzberg J
Front Cell Neurosci · 2026 · PMID 42179844 · Full text
Neuronal responses are inherently variable and similar characteristics can arise from multiple combinations of cellular parameters, with electrical diversity and variable branching patterns contributing to degeneracy. Th...
Neuronal responses are inherently variable and similar characteristics can arise from multiple combinations of cellular parameters, with electrical diversity and variable branching patterns contributing to degeneracy. The contribution of morphological details, such as the diameter and length of dendritic branches, to response variability and degeneracy in neurons with a given branching pattern remains unclear. We address this question by using a model database approach with spatially extended, conductance-based compartmental models to study the variability of response features, such as resting membrane potential, input resistance, spike count, first spike latency, spike height, and spike width. Using 15 reconstructed morphologies of leech touch cells with fixed branching patterns, we identified thousands of parameter sets that were consistent with the experimentally measured response features in all the tested morphologies. Even when the electrical parameters were kept equal across reconstructed morphologies, variability in response features arose from the morphological details, beyond the well-known dependencies on the total membrane area and input resistance. Varying the spatial distribution of ion channels revealed that spike response features are influenced by the location of spike initiation zones with higher conductance density. Nevertheless, biologically plausible responses can arise from distinct locations of spike initiation zones, or even with a homogeneous distribution of ion channels. Furthermore, comparing the simulated spike responses from two morphological subtypes of leech touch cells revealed that the previously published systematic differences cannot be explained by the morphological differences alone. A larger total conductance of voltage-gated ion channels was required to reproduce the experimental finding of an increased spike count and a larger spike amplitude in the larger morphological subtype. In conclusion, morphological details interact with branching patterns, ion channel distribution and electrical properties, contributing significantly to the variability and degeneracy of neuronal responses.
Route selection impairment and microglia activation in a rodent model of attention-deficit hyperactivity disorder.
Skubic SG, Wynter Z, Kramer MM … +1 more , Hales JB
Front Cell Neurosci · 2026 · PMID 42164021 · Full text
INTRODUCTION: The ability to remember locations of objects and make spatial decisions is critical when navigating an environment. Such tasks, however, can be difficult for individuals with certain neurological conditions...
INTRODUCTION: The ability to remember locations of objects and make spatial decisions is critical when navigating an environment. Such tasks, however, can be difficult for individuals with certain neurological conditions, such as attention deficit hyperactivity disorder (ADHD). The traveling salesperson problem (TSP), a naturalistic spatial foraging task, has been effectively used to examine these spatial navigational processes in rodents, as this optimization task requires subjects to identify the shortest route of travel between a certain number of targets in an open arena. Previous studies using the TSP task have found that rats with hippocampal or medial entorhinal cortex lesions are impaired on measures of spatial memory, but not spatial decision-making or route selection. METHODS: The current study examined the performance of male and female spontaneously hypertensive rats (SHR), the most widely used rodent model of ADHD, relative to their control model, Wistar Kyoto (WKY) rats, on the TSP task. RESULTS: Our behavioral findings suggest that both male and female SHRs have greater deficits in route selection compared to WKY rats, but they show intact performance on measures of spatial memory. We also examined microglia expression as a marker of neuroinflammation in the prefrontal cortex, hippocampus, and medial entorhinal cortex. SHRs had a greater percentage of hypertrophic microglia, indicating extended periods of inflammation or activation, in the infralimbic area of the prefrontal cortex and in the dentate gyrus. Within the dentate gyrus, the female SHRs showed an increased percentage of hypertrophic microglia compared to female WKY rats. DISCUSSION: This study expands on existing literature within ADHD-model male and female rats by exploring their ability to effectively route optimize using a naturalistic task.
Identity crisis: exploring the boundaries of cell type identification in the age of single-cell transcriptomics.
Yang S, Tyagi S, Rosenmund C … +1 more , Herman MA
Front Cell Neurosci · 2026 · PMID 42164020 · Full text
The rise of single-cell transcriptomics and comprehensive reference atlases promised a unifying molecular framework to classify cell identity. Yet transcriptomic identities are often interpreted outside the environmental...
The rise of single-cell transcriptomics and comprehensive reference atlases promised a unifying molecular framework to classify cell identity. Yet transcriptomic identities are often interpreted outside the environmental contexts in which they arise. Here, we analyzed primary cortical cultures, which lack native tissue architecture, to compare their transcriptional profiles to multiple mouse cortical reference datasets. We found that while core molecular signatures for major neuronal subclasses are largely preserved , the loss of structure triggers high transcriptional divergence associated with metabolic and physiological state. We also identified clusters that consistently show low confidence in the classification tool. These ambiguous populations express incomplete canonical marker profiles resulting from a lack of structural cues necessary for full maturation. These observations suggest that while transcriptomic reference frameworks capture major aspects of neuronal identity, their interpretation can become less certain when cells are profiled outside their native environment. Our findings highlight the importance of considering environmental context when interpreting transcriptome-based cell type annotations and provide a resource for understanding how neuronal transcriptional programs are reshaped .
Retraction: Differential expression of sirtuins in the aging rat brain.
Frontiers Editorial Office
Front Cell Neurosci · 2026 · PMID 42158335 · Full text
[This retracts the article DOI: 10.3389/fncel.2015.00167.].
[This retracts the article DOI: 10.3389/fncel.2015.00167.].
A history of maternal separation drives systemic aging-associated signatures in middle-aged male rats.
Chaudhari PR, Chaurasiya AH, Vaidya ADB … +2 more , Kulkarni MJ, Vaidya VA
Front Cell Neurosci · 2026 · PMID 42158334 · Full text
Early adversity programs induce changes that can accelerate biological aging. Using the early stress model of maternal separation (MS), we assessed oxidative, metabolic, and biochemical consequences in serum derived from...
Early adversity programs induce changes that can accelerate biological aging. Using the early stress model of maternal separation (MS), we assessed oxidative, metabolic, and biochemical consequences in serum derived from middle-aged male rats to investigate systemic correlates of physiological aging in MS animals. We noted significant increases in serum corticosterone in middle-aged MS male rats, accompanied by reduced serum levels of trophic factors, brain-derived neurotrophic factor (BDNF), and insulin-like growth factor-1 (IGF1). We also found increased oxidative stress markers, such as oxidized low-density lipoprotein (Ox-LDL) in MS animals, concomitant with reduced antioxidant enzyme activity of superoxide dismutase (SOD) and catalase. The serum lipid profile analysis revealed metabolic dysregulation with increased triglyceride, total cholesterol, and LDL levels. Furthermore, mass spectrometric analysis indicated a significant increase in advanced glycation end-product (AGE) modified serum albumin peptides in middle-aged MS male rats, accompanied by enhanced expression of the precursor for AGEs, methylglyoxal (MGO), and the soluble form of the receptor for AGEs (sRAGE). Collectively, these findings suggest that the early stress of MS evokes long-lasting systemic changes that persist into middle age and reflect glyco-oxidative damage, dyslipidemia, disrupted trophic factor signaling, and enhanced accumulation of AGEs, which could contribute mechanistically to cellular and physiological aging processes.
Live-cell physiology in human brain tissue culture-the potential, the challenges, and the lessons learned.
Oudart M, van Loo KMJ, Kronenberg-Versteeg D
Front Cell Neurosci · 2026 · PMID 42146937 · Full text
A growing number of studies are now utilizing human organotypic brain slice cultures (OBSC), enabled by improved long-term culture protocols that support the investigation of human-specific cellular physiology. Human OBS...
A growing number of studies are now utilizing human organotypic brain slice cultures (OBSC), enabled by improved long-term culture protocols that support the investigation of human-specific cellular physiology. Human OBSC offer the unique advantage, that they preserve the connectivity and microenvironment of human brain tissue while remaining experimentally tractable for live functional assays. However, methods established in rodent brain slice cultures, such as viral labeling, genetic manipulation, and long-term transduction strategies, do not readily translate to human tissue due to differences in viral tropism, tissue heterogeneity, and limited survival in culture. In this review, we highlight key historical developments and provide an overview of current best practices of human brain tissue culture. We provide an overview of live cell-specific labeling strategies, including viral approaches, as well as current and emerging technologies for functional manipulation and for investigating disease-related pathologies. Throughout, we integrate insights gained from mouse models and discuss how these technologies could potentially be adapted and leveraged for human OBSCs. Beyond methodological approaches, we also address the challenges and limitations inherent to working with human brain tissue. Together, these advances position human OBSCs as a powerful platform to bridge the gap between reductionist systems and the living human brain.
A sequential multimodal framework for spinal cord regeneration.
Sos EB
Front Cell Neurosci · 2026 · PMID 42137554 · Full text
This hypothetical study explores a potential therapeutic strategy for patients with recent complete spinal cord injuries (≤6 weeks since injury approximately). We review current literature and identify five key determina...
This hypothetical study explores a potential therapeutic strategy for patients with recent complete spinal cord injuries (≤6 weeks since injury approximately). We review current literature and identify five key determinants of regenerative failure: inflammation, glial scar formation, deficit in molecular guidance, loss of structural guidance, and persistence of Wallerian debris. Although each of these barriers can be addressed by existing interventions, their efficacy depends partially on a constrained sequence of application. Based on this, a temporally orchestrated strategy is proposed, comprising early immunomodulation to stabilize the lesion environment, mechanical realignment combined with implantation of a temporary extracellular matrix to restore structural continuity, sustained molecular guidance and matrix remodeling to guide axonal growth. The proposed framework offers a mechanistically integrated and testable hypothesis for promoting functional spinal cord regeneration.
Mesenchymal vs. induced pluripotent stem cells: potential for spiral ganglion neuron regeneration in auditory neuropathy.
Aasar B, Veret D, Zine A
Front Cell Neurosci · 2026 · PMID 42137553 · Full text
Auditory neuropathy is a distinct form of sensorineural hearing loss characterized by dysfunction or degeneration of primary auditory neurons, also known as spiral ganglion neurons (SGNs), which transmit acoustic informa...
Auditory neuropathy is a distinct form of sensorineural hearing loss characterized by dysfunction or degeneration of primary auditory neurons, also known as spiral ganglion neurons (SGNs), which transmit acoustic information from the cochlea to the brain. Increasing evidence indicates that SGNs are particularly susceptible to degeneration induced by noise exposure, ototoxic agents, genetic mutations, or aging, often preceding the loss of cochlear mechanosensory hair cells, and thus represents a critical target for regenerative intervention for auditory neuropathy. Stem cell-based approaches have emerged as promising strategies to restore auditory nerve function. In particular, the generation of otic neuronal progenitors (ONPs) capable of replacing damaged SGNs offers a translationally relevant avenue for therapy. Among candidate sources, mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs) offer distinct biological and translational advantages. iPSCs provide robust pluripotency and developmental recapitulation capacity, enabling efficient differentiation toward otic neuronal lineages, whereas MSCs offer immunomodulatory properties and paracrine neurotrophic support with lower tumorigenic risk. This mini-review critically compares MSC and iPSC-derived ONPs in terms of differentiation efficiency, neuronal maturation, integration potential, immunogenicity, and scalability. We further discuss emerging complementary strategies, including ONP transplantation, glial cell reprogramming and extracellular vesicle-based therapies. Together, these approaches highlight converging regenerative paradigms aimed at restoring auditory neuron function in neuropathic hearing loss.
Retraction: 2-Methoxyestradiol alleviates neuroinflammation and brain edema in early brain injury after subarachnoid hemorrhage in rats.
Frontiers Editorial Office
Front Cell Neurosci · 2026 · PMID 42125627 · Full text
[This retracts the article DOI: 10.3389/fncel.2022.869546.].
[This retracts the article DOI: 10.3389/fncel.2022.869546.].
CNTNAP2: isoform- and context-specific functions in neurological disorders and cancer.
Ye Y, Zhu L, Wang D
Front Cell Neurosci · 2026 · PMID 42110583 · Full text
Contactin-associated protein-like 2 () is one of the largest and most evolutionarily conserved genes in the human genome that increasingly recognized as a pleiotropic and context-dependent regulator of human disorders. G...
Contactin-associated protein-like 2 () is one of the largest and most evolutionarily conserved genes in the human genome that increasingly recognized as a pleiotropic and context-dependent regulator of human disorders. Genetic, immunological, and transcriptomic studies have implicated in a broad spectrum of neurological and psychiatric disorders, autoimmune encephalitis, and cancer. Early work focused primarily on the full-length isoform , which encodes CASPR2 or CNTNAP2, and plays essential roles in neuronal development, axon-glia interactions, synaptic transmission, interneuron maturation, and maintenance of excitatory-inhibitory balance. Disruption of these functions contributes to impaired cortical connectivity and network dysfunction in neurodevelopmental disorders. Recent discoveries have substantially expanded this view by revealing isoform-specific and proteolytic fragment-dependent functions of CNTNAP2. Proteolytic processing of CNTNAP2 generates bioactive extracellular and intracellular fragments that regulate calcium homeostasis, gene expression, and neuronal network activity. In parallel, the short isoform has recently emerged as an oncogenic driver in oral squamous cell carcinoma, where its selective upregulation amplifies EGFR-E2F1 signaling and promotes tumor progression. This review synthesizes current knowledge of CNTNAP2 biology, highlighting isoform- and context-specific mechanisms and outlining key unanswered questions relevant to both neurological disease and cancer.
Editorial: Expanding the glial frontiers: development, function and pathophysiology.
Kim DW
Front Cell Neurosci · 2026 · PMID 42110582 · Full text
Abstract loading — click title to view on PubMed.
Method for the simultaneous isolation of primary astrocytes and microglia from the neonatal rats cerebral cortex.
Zhang K, Wu S, Zeng Y … +3 more , Wu X, Qian M, Xu K
Front Cell Neurosci · 2026 · PMID 42094084 · Full text
OBJECTIVE: To establish a protocol for the simultaneous isolation and high-purity purification of primary astrocytes and microglia from neonatal rats cerebral cortex. METHODS: Single-cell suspensions were prepared from c...
OBJECTIVE: To establish a protocol for the simultaneous isolation and high-purity purification of primary astrocytes and microglia from neonatal rats cerebral cortex. METHODS: Single-cell suspensions were prepared from cerebral cortices of postnatal day 2 (P2) rat pups. Fibroblasts were pre-removed using differential adhesion techniques. Mixed glial cultures were maintained with graded serum (from 10% to 5% to 2% FBS) to suppress fibroblast proliferation. On day 14, microglia were isolated by constant temperature shaking (200 rpm, 12 h, 37 °C), followed by manual agitation of remaining adherent cells to purify astrocytes. Cell purity was assessed by immunofluorescence (Iba1 and GFAP) and validated by multicolor flow cytometry (CD11b/CD45; ACSA-2) and ER-TR7 fibroblast exclusion staining. Cell viability was evaluated by trypan blue exclusion and CCK-8 assay. Microglial morphology was quantified by cell body area, circularity index, and primary process number. RESULTS: Day 14 was identified as the optimal separation time point. Immediately post-shaking, microglia purity (Iba1) reached 98.6% ± 1.1%, and astrocyte purity (GFAP) was 98.4% ± 1.7%. After subsequent purification culture, these values increased to 98.98% ± 1.21% and 98.81% ± 2.38%, respectively. Dual-label immunofluorescence confirmed minimal cross-contamination, with Iba1/GFAP dual-positive cells constituting <1% in both populations. Multicolor flow cytometry corroborated these findings, yielding CD11b purity of 97.12% ± 1.58% for microglia (with 95.37% ± 1.84% classified as CD11b/CD45^low homeostatic microglia) and ACSA-2 purity of 94.65% ± 2.73% for astrocytes. No unequivocal ER-TR7 fibroblasts were identified in either purified population. Microglial morphology progressively transitioned from amoeboid (Day 0: area 173.5 ± 32.8 μm; circularity 0.847 ± 0.058; processes 0.8 ± 0.4) to ramified (Day 5: area 418.2 ± 68.3 μm; circularity 0.438 ± 0.095; processes 4.3 ± 0.8 per cell). Cell viability remained above 92% following key procedural steps and recovered to over 95% post-purification; CCK-8 assay confirmed full metabolic recovery. CONCLUSION: This study establishes a combined method utilizing graded serum and constant temperature shaking for glial cell isolation, enabling simultaneous acquisition of both major glial cell types from a single animal. This cost-effective protocol provides a practical tool for functional studies of neuroglial cells.
Non-cell autonomous downregulation of the purinergic receptor P2Y1R promotes neuroprotection after ischemic injury.
Spagnuolo G, Iacovitti L
Front Cell Neurosci · 2026 · PMID 42094083 · Full text
Current ischemic stroke treatments largely focus on exogenous means of neural repair, with endogenous mechanisms being less understood. Here, we examine the cellular and molecular foundation of an endogenous neuroprotect...
Current ischemic stroke treatments largely focus on exogenous means of neural repair, with endogenous mechanisms being less understood. Here, we examine the cellular and molecular foundation of an endogenous neuroprotective mechanism using the stroke model oxygen-glucose deprivation (OGD). We demonstrate that after OGD, dying cortical neurons release ATP to activate microglia. There is a simultaneous increase in microglial release of B-NGF and IL-2, increased TrkA receptor expression on astrocytes, and a consequent downregulation in astrocyte P2Y1 receptors (P2Y1R), resulting in a decline in neuronal intracellular calcium levels and enhanced neuronal survival. This neuroprotective effect is mimicked when P2Y1R expression is directly knocked out in astrocytes or when exogenous microglial activators IL2 or NGF are added in place of microglia. Conversely, these neuroprotective effects are prevented by blockade of microglial activation or inhibition of TrkA or IL-2 receptors. Pharmacological buffering of intracellular Ca with BAPTA-AM recapitulated the neuroprotective effect, whereas NMDA receptor blockade with Dizocilpine maleate did not, indicating that neuronal survival is mediated by reduced intracellular Ca accumulation through an NMDA receptor-independent mechanism. Together, these results suggest the downregulation of P2Y1R in astrocytes by activated microglia is a critical endogenous neuroprotective mechanism after ischemic injury. By understanding these inherent non-cell autonomous mechanisms and their molecular mediators, it may be possible to improve intrinsic neuroprotection and recovery from stroke.
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