Cellular and Molecular Neurobiology最新文献

Glioblastoma multiforme (GBM) is a complex and aggressive central nervous system (CNS) tumor that has a poor prognosis, and restricted therapeutic options are available despite the increasing research conducted. Moreover, the cells in our body package microRNAs, ubiquitous modulators of numerous biological processes, into exosomes for cell-to-cell signaling. Indeed, exosomal miRNAs contribute to several aspects of glioma, such as development, occurrence, metastasis, and immune evasion. Additionally, exosomal miRNAs play a key role in cellular functions and glioma pathogenesis by regulating numerous pathways, including the Wnt/β-catenin, PTEN/PI3K/Akt, EGFR/MAPK, notch signaling, and NF-κB. Notably, exosomal miRNAs are recognized to have promising potential in clinical applications; in fact, exosomal miRNAs are emerging biomarkers for glioma diagnosis and prognosis and are additionally considered as putative therapeutic candidates by inhibiting tumor progression, occurrence, and metastasis. This review presents the current knowledge regarding clinical potential and application of exosomal miRNAs in glioma, as well as the miRNA-mediated regulatory network underlying glioma immunopathogenesis.

Synaptic formation, the cornerstone of neurological function, underpins complex behaviors and cognitive processes, with structural/functional aberrations implicated in neurodevelopmental disorders and neurodegenerative pathologies. Synaptogenesis involves dynamic interplay between cell adhesion molecules (CAMs) and extracellular matrix (ECM) components, which collectively regulate neuronal connectivity and plasticity. Matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMPs), emerge as critical regulators of these processes through ECM remodeling and modulation of cell surface receptor signaling. This review synthesizes current understanding of ECM-TIMP-MMP axes in synaptic development, highlighting their dual roles in physiological plasticity and pathological disruption across neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease), neuro-oncological disorders, and neuroinflammatory conditions. By dissecting the context-dependent functions and therapeutic implications of TIMP family members in synaptic maintenance and disease progression, this work provides a conceptual framework for advancing TIMP-based neurotherapeutic strategies and a theoretical basis for future exploration of TIMP as a potential therapeutic target for neurological disorders.

Lead (Pb) is a hazardous heavy metal frequently used because it is readily available and inexpensive. Due to contaminated soil, dust, and items like paints and batteries, lead exposure is still an issue of concern in many nations. There is no known safe threshold of exposure, and it can have serious adverse effects on human health. Exposure to lead has been linked to detrimental effects on the developing nervous system of both children and adults. Alzheimer's disease (AD) is the most prevalent type of dementia affecting adults over the age of 65, resulting in a decrease in memory and thinking skills. In this review, we describe the role of lead in exacerbating the build-up of hyperphosphorylated tau proteins and formation of amyloid-β (Aβ) plaques, major neurotoxicants which can impair neuronal function leading to AD. We highlight the effect of developmental and lifelong lead exposure on various gene expression changes resulting in the formation of the neurotoxicants responsible to AD. Understanding the mechanisms related to Aβ plaques and neurofibrillary tangles (NFTs) formation serves as a novel approach to identify biomarkers for lead-induced AD and developing therapeutic interventions. Lead exposure has been related to adverse effects on the developing neurological systems of both adults and children.

The dentate gyrus of the hippocampus develops through complex cellular migrations and differentiations, which have been primarily characterized using genetic lineage tracing approaches. Through systematic application of in utero electroporation across developmental stages, we found that labeling was most effective at embryonic day 12.5 (E12.5), as earlier stages resulted in embryonic lethality while later stages showed markedly reduced efficiency. To directly compare these cells with genetically-defined progenitor populations, we established a novel dual-visualization system, combining electroporation with transgenic reporter mice (Gfap-GFP). This approach revealed marked differences in developmental trajectories: Gfap-GFP+ cells maintain undifferentiated neural stem/progenitor characteristics with persistent Sox2 expression, while E12.5-labeled cells predominantly differentiate into Prox1-positive granule cells by E18.5. These early-labeled cells display characteristic migration patterns, with 60.9% differentiating into Prox1-positive granule cells compared to only 22.8% of Gfap-GFP+ cells (P < 0.001), exclusively following an outside-in trajectory to establish the initial framework of the granule cell layer, without reaching the tertiary dentate matrix. In contrast, Gfap-GFP+ cells populate the tertiary dentate matrix and serve as a sustained progenitor reservoir. Molecular marker analysis reveals sequential expression of Sox2, Tbr2, and Prox1, demonstrating progressive differentiation during migration. Our findings identify an early-differentiating subset of dentate progenitors with accelerated neurogenic progression, revealing previously unrecognized temporal and functional heterogeneity in dentate development. This study demonstrates how stage-specific in utero electroporation can complement genetic approaches by uncovering progenitor subsets with rapid differentiation kinetics, providing new insights into the cellular diversity that shapes hippocampal structure and function.

Autism spectrum disorders (ASD) are neurodevelopmental conditions involving impaired neuronal processes such as connectivity, synaptogenesis, and migration. Prenatal exposure to valproic acid (VPA), an anticonvulsant and mood stabilizer, is linked to increased ASD risk, with timing as a key factor. However, the molecular mechanisms of VPA-induced neurodevelopmental disruptions remain unclear. Building on our previous study, which characterized VPA-induced prenatal and postnatal ASD models with impaired social behavior, repetitive patterns, and altered brain connectivity, this study examines molecular changes in neurogenic brain regions. We analyzed the prefrontal cortex, hippocampus, and subventricular zone at key developmental time points (postnatal days 14 and 21), assessing neurotrophins (BDNF, Nt-3, IGF-β, GDNF) and markers of cell migration (DCX), differentiation (NeuN, GFAP), and synaptogenesis (synaptophysin). Our findings show that both prenatal and postnatal VPA exposure disrupt neurogenesis, with prenatal effects being more severe and persistent. Prenatal VPA significantly reduced BDNF in the subventricular zone and DCX in the olfactory bulb, suggesting impaired migration, while morphological analysis revealed thickening of ventricular lateral wall and disrupted cellular organization. Postnatal exposure led to transient neurotrophin changes, including delayed IGF-β production and an abnormal rise of BDNF levels. Elevated GFAP and reduced NeuN or synaptophysin in the prefrontal cortex, alongside increased neuronal markers in the hippocampus, suggest region-specific neuroglial imbalances. These findings highlight the stage-dependent vulnerability of the developing brain to VPA exposure, revealing distinct mechanisms of disruption in prenatal and postnatal administration. They underscore the need to minimize exposure risks during late gestation and early postnatal periods, which are crucial for neurodevelopment.

The nervous system exhibits remarkable adaptability through neuroplasticity, which allows for structural and functional changes in response to intrinsic and extrinsic stimuli. This dynamic process underpins synaptic formation, elimination, learning, memory, and brain recovery after neurological insults. However, neuroplasticity can be compromised by neurotropic viral infections, which present significant challenges to the central nervous system (CNS). Viruses infiltrate the CNS through various mechanisms, including peripheral nerves, disruption of the blood-brain barrier (BBB), and evasion of the immune system, leading to acute or chronic neuronal pathologies. Moreover, these infections may trigger encephalitis, neuroinflammation, and synaptic dysfunction, thereby impairing neural circuits and compromising brain function. Persistent viral infection and chronic responses further exacerbate neuronal damage through oxidative stress, excitotoxicity, and disruption of neural progenitor cells. Collectively, these effects hinder neuroplasticity, resulting in cognitive deficits, behavioral changes, and long-lasting structural alterations. Understanding the mechanisms by which neurotropic viruses impair neuroplasticity is crucial for developing targeted therapeutic interventions. Strategies aimed at addressing viral persistence, mitigating inflammation, and promoting synaptic repair are critical to preserving brain health and functionality. This review provides a comprehensive overview of virus-induced neuronal pathologies and their effects on neuroplasticity, highlighting the importance of innovative treatments to enhance CNS resilience and recovery in affected individuals.

Multiple sclerosis (MS) is an inflammatory disease that affects the central nervous system, characterized by myelin damage caused by immune dysfunction and genetic factors. Nevertheless, the role of peripheral blood and immune cells in the development of MS remains poorly defined. We employed a two-sample Mendelian randomization (MR) approach, analyzing data from 91 blood cell perturbation phenotypes and 731 immune cell traits. Causal inference was conducted using multiple robust MR techniques, including inverse variance weighting, with mediation analysis and sensitivity tests (Cochran's Q, MR-Egger intercept, and leave-one-out analysis) performed to validate the results.The present study identified significant associations between 9 blood cell perturbation phenotypes and 34 immune cell traits with MS risk. The effect of neutrophil disturbances on MS was partially mediated by HLA-DR expression on B cells, with a mediation proportion of approximately 16.38%. Moreover, sensitivity analyses confirmed the robustness of these findings.This study suggests that specific blood cell perturbations may increase MS risk and reveals the mediating role of immune cells between blood and nervous system disturbances. In addition, we provide genetic evidence for understanding MS immune mechanisms, which could help guide the development of targeted immunotherapies.

The basolateral amygdala (BLA) serves in the evaluation of reward. However, the causal molecular substrates in the BLA necessary for reward seeking behaviour are largely unknown. Reward conditioning induces long-lasting changes in epienzymes in limbic areas, including the amygdala. The current study probed the role of histone arginine methylation as a novel epigenetic mechanism in neuropeptide Y (NPY) gene regulation in the BLA during reward and reinforcement. For reward conditioning, adult Wistar rats were trained to self-administer sucrose pellets in a nose-poke operant chamber. Reward conditioning increased protein arginine methyltransferase 4 (PRMT4) and NPY in the BLA. Moreover, after operant conditioning, histone arginine methylation (H3R17me2a) and PRMT4 occupancy at the NPY promoter were heightened. PRMT4 was predominantly colocalised in the nucleus of the NPY-expressing cells in the BLA. Intra-BLA administration of specific siRNA or inhibitor of PRMT4 after conditioning waned the nose-poke activity, which was further reinstated during the subsequent 5 days. These effects of PRMT4 repression were correlated with the NPY expression and H3R17me2a levels at the NPY promoter. Furthermore, NPY peptide administration after PRMT4 siRNA or inhibitor infusion in BLA restored the nose-poke activity. PRMT4 is known to interact with CREB-binding protein (CBP). Therefore, co-occupancy of PRMT4 and CBP resulted in heightened histone acetylation (H3K14ac) in the conditioned rats. The current study suggests a pivotal role of PRMT4-mediated histone arginine methylation in NPY gene expression in the amygdala necessary for the reward-seeking behaviour.

This study evaluated the protective effects of celecoxib on epilepsy and explore its potential involvement in regulating pyroptosis and the high mobility group box 1 (HMGB1)/Toll-like receptor 4 (TLR4) signaling pathway. Adult male Sprague-Dawley rats were injected with ferrous chloride (FeCl₂) with or without celecoxib for 7 consecutive days. After sacrifice, tissues were collected for neurological function assessments, magnetic resonance imaging, and multiple tissue analyses. Intracerebral injection of FeCl₂ in rats induced severe seizures, microglial recruitment and polarization, ferroptosis, pyroptosis, and inflammation in the frontal cortex. In the hippocampus, FeCl₂ injection led to neuronal loss, reduced synaptic complexity, and aberrant HMGB1 expression. Celecoxib treatment delayed seizure onset and significantly reduced the severity and duration of seizures, the extent of injury, and neurological impairments caused by FeCl₂ exposure. These effects were mediated through the suppression of HMGB1/TLR4 signaling and inhibition of key pro-inflammatory cytokines. Celecoxib treatment mitigated neuronal loss, improved synaptic complexity, stabilized microglial activity, inhibited astrocyte proliferation, and modulated HMGB1 expression. In conclusion, celecoxib effectively attenuated FeCl₂-induced inflammation and neural injury partially by inhibiting the HMGB1/TLR4 pathway, thereby suppressing pyroptosis and reactive gliosis. These effects improved seizure, highlighting the therapeutic potential of celecoxib for managing epilepsy following hemorrhagic brain injury.

Neurodegeneration involves the progressive deterioration of neuronal structure and function, leading to deficits in cognition, motor skills, and other neurological processes. Parkinson's disease (PD) is notably prevalent among neurodegenerative disorders, characterized by dopaminergic neurodegeneration, protein misfolding, and an inflammatory brain environment. Despite advancements in understanding its pathophysiology, PD and other neurodegenerative conditions still lack effective disease-modifying therapies. This shortfall highlights the need for novel, multifactorial approaches to treatment. Recent research has spotlighted the gut-brain axis as a significant player in neurological health, particularly through the activity of gut-derived short-chain fatty acids (SCFAs). These microbial metabolites, primarily acetate, propionate, and butyrate, are produced via the fermentation of dietary fibers and are vital for maintaining intestinal and neural homeostasis. SCFAs exert anti-inflammatory effects, preserve blood-brain barrier integrity, and modulate neurotransmitter systems. Among them, butyrate shows notable neuroprotective capabilities, including histone deacetylase inhibition and mitochondrial enhancement. Disruption in SCFA production has been associated with PD progression, further underscoring their relevance. This review explores the mechanistic roles of SCFAs in modulating neurodegeneration, with an emphasis on PD. SCFA-based strategies offer a promising adjunctive route to restoring microbial balance, mitigating neuroinflammation, and safeguarding neurological function in neurodegenerative disorders.