Frontiers in Cellular Neuroscience最新文献

[This corrects the article DOI: 10.3389/fncel.2025.1719532.].

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.

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. Aβ₄₂ 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.

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.

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.

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.

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.

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.

Preterm birth substantially elevates the risk of neurological and cognitive disorders. Recent evidence suggests that the abrupt loss of placental support, particularly the cessation of neurotrophic and neuroprotective hormones, alters neurodevelopmental trajectories and may contribute to neurodevelopmental risk associated with prematurity. Our study investigates how the placental steroid hormone, allopregnanolone (ALLO), affects cerebral cortex development using human cortical organoid models. Our findings reveal that while ALLO exposure produces modest effects on overall cortical development, its withdrawal specifically disrupts GABAergic but not glutamatergic neuronal development. These results demonstrate that placental hormones, including ALLO, may target specific neuronal populations critical for cortical function, identifying potential therapeutic interventions following placental loss in human preterm neonates.

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 (Ca²⁺) homeostasis, ATP production, and apoptotic signaling. Disruptions in Ca²⁺ 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.