Developmental Neurobiology最新文献

Neuroinflammation, characterized by activation of immune cells and release of inflammatory mediators in the central nervous system, plays a critical role in the onset and progression of epilepsy. Elevated inflammatory activity has been documented in both peripheral blood and epileptogenic brain tissue, implicating mediators such as interleukin-1β (IL-1β), IL-6, tumor necrosis factor-alpha, and glutaminergic and MDMA pathways. Beyond seizure generation, neuroinflammation may contribute to psychiatric comorbidities, including anxiety and depression. Anti-inflammatory strategies, encompassing pharmacologic agents such as glucocorticoids, adrenocorticotropic hormone, and vigabatrin, as well as dietary approaches like the ketogenic diet, have demonstrated reductions in seizure frequency and inflammatory signaling. Leukotriene receptor antagonists, established in asthma therapy, show promise in animal models and retrospective human studies, particularly in older adults who exhibit a pro-inflammatory state due to immunosenescence. Physical activity exerts systemic and central anti-inflammatory effects, modulating gene expression, metabolism, antioxidant defense, and neuroprotective pathways. Preclinical evidence demonstrates that endurance and swimming exercises can reduce seizure susceptibility, hippocampal inflammation, oxidative stress, and apoptotic signaling, while improving blood–brain barrier integrity. Human studies remain limited but suggest that regular physical activity may lower the risk of focal epilepsy. Collectively, these findings support the potential of integrating exercise-based interventions to mitigate neuroinflammation and seizure burden, particularly in aging populations. Further research is needed to clarify underlying mechanisms and optimize protocols for clinical translation.

The SET domain containing the 2 (SETD2) gene encodes a histone methyltransferase responsible for H3K36me3 modification, playing key roles in transcriptional regulation, RNA splicing, and DNA repair. Pathogenic variants in SETD2 have been linked to variable phenotypes, including Luscan–Lumish syndrome (LLS, OMIM #616831), autosomal dominant intellectual developmental disorder 70 (MRD70, OMIM #620157), and Rabin–Pappas syndrome (RAPAS, OMIM #620155). Defining the severity of intellectual disability/developmental delay caused by SETD2 variants is important for accurate genetic counseling. This study aims to present a patient carrying a novel de novo nonsense variant in the SETD2 gene and to expand the clinical phenotype spectrum associated with SETD2 variants. A 17-year-old male with dysmorphic features, epilepsy, attention deficit and hyperactivity disorder (ADHD), and moderate intellectual disability underwent a detailed clinical and genetic evaluation. A novel de novo heterozygous nonsense variant in the SETD2 gene, NM_014159.7:c.7084C>T (NP_054878.5:p.Gln2362Ter), was identified by whole-exome sequencing. This variant was classified as likely pathogenic according to American College of Medical Genetics and Genomics (ACMG) guidelines. The patient exhibited clinical features overlapping with LLS. Further research is warranted to elucidate the mechanistic differences underlying various SETD2 variants, which will be essential for improving our understanding of SETD2-related disorders and for providing accurate genetic counseling and targeted management strategies.

Inflammatory bowel disease (IBD) is an enduring inflammatory complaint with extraintestinal consequences, including autism spectrum disorder (ASD). This experiment was directed to test the influence of maternal separation (MS) stress on the comorbidity of ASD-like behaviors provoked following experimental colitis in male mice, emphasizing the relevance of hippocampal structure, mammalian target of the rapamycin (mTOR), and neuroinflammation. The 32 male Naval Medical Research Institute (NMRI) mice were randomly assigned into four groups, including the MS mice with or without induction of colitis and control mice with or without induction of colitis. Seven days after induction of colitis using acetic acid, mice subjected to the behaviors related to autism, including sociability and social preference indexes, passive avoidance memory, and repetitive and anxiety-like behaviors, were assessed. Then, the colon and hippocampus were dissected out. Diameter and percent of dark neurons of the CA1 and CA3 in the hippocampus plus histopathological change in the colon were assessed. RT-PCR measured TLR4, TNF-α, IL-1β, and mTOR mRNA expression in the hippocampus. Outcomes revealed that MS amplified the negative effects of colitis on related behaviors to autism. MS augmented effect of colitis on reduction of diameters and enhancement of dark neurons in the CA1 and CA3 parts along with histopathological changes of the colon. The hippocampal mRNA expression of TLR4, IL-1β, TNF-α, and mTOR more increased in the group that underwent both MS and colitis. These findings, partially, suggest that MS intensified the influence of colitis on ASD-like phenotype, reinforcing, in part, the role of hippocampal neuroinflammation, mTOR as well as structural hippocampal changes.

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental condition defined by social deficits, stereotypical or repetitive behaviors, and anxiety. This study evaluates the therapeutic potential of transauricular vagal nerve stimulation (tVNS) in a valproic acid (VPA)-induced mouse model of ASD. The study comprised three groups: the control + sham (saline-treated offsprings receiving sham stimulation), the autistic + sham (VPA-treated offspring receiving sham stimulation), and the autistic + tVNS (VPA-treated offsprings receiving tVNS). Male C57BL/6 mice exposed to VPA on embryonic day 12.5 were evaluated for behavioral and neurobiological alterations. tVNS was applied twice weekly for 3 weeks to investigate its effects on sociability, anxiety-like behaviors, neurogenesis markers, and apoptosis pathways. Behavioral testing, including the three-chamber test, mirrored chamber test, open field test, and elevated plus maze, revealed that tVNS significantly improved sociability and social preference indices, reduced social anxiety, and decreased general anxiety-like behaviors in VPA-induced mice. Histological and immunohistochemical analyses have shown a decrease in neuron density, brain-derived neurotrophic factor (BDNF), and doublecortin (DCX) expression in the hippocampus, amygdala, and prefrontal cortex of VPA-induced mice. Additionally, the increase in caspase-3 immunoreactivity indicates increased apoptosis. tVNS treatment restored BDNF and DCX levels, promoting neurogenesis and synaptic plasticity while significantly reducing caspase-3-mediated apoptosis in affected brain regions. These findings suggest that tVNS may counteract the neural and behavioral deficits associated with ASD by modulating neurogenesis, neuronal plasticity, and apoptosis. The study highlights tVNS as a potential therapeutic intervention for ASD, emphasizing its role in targeting both behavioral alterations and underlying neurobiological mechanisms.

Transition metal complexes (TMCs) have emerged as promising agents in neurotherapeutics due to their redox activity, coordination flexibility, and ability to interact with biomolecular targets. However, their cytotoxic effects on neural tissues remain insufficiently understood, posing challenges for safe and targeted applications. Computational approaches provide powerful tools for unraveling the mechanisms underlying TMC-induced cytotoxicity, enabling the prediction of biological behavior at the molecular level. This study explores how advanced in silico methods, such as molecular docking, density functional theory (DFT), and molecular dynamics (MD) simulations, are applied to assess the structure, reactivity, and interaction profiles of TMCs in neurological contexts. Particular focus is placed on modeling neurotoxicity mechanisms, evaluating blood–brain barrier penetration, and identifying structure–activity relationships (SARs) relevant to neurodegenerative diseases and pediatric brain cancers. Comparative analyses across different metal centers and ligand frameworks are presented, revealing how variations in electronic structure influence biological outcomes. Moreover, limitations of current computational methodologies are addressed, along with challenges in accurately modeling the neural microenvironment. Opportunities for future research include the integration of machine learning to enhance predictive accuracy, automate compound screening, and guide rational design of neuroactive metal-based drugs. The review also emphasizes the need for standardized protocols to improve reproducibility and biological relevance in computational neurotoxicology. By aligning the capabilities of computational chemistry with the demands of neurobiology, this study highlights a strategic framework for advancing safe, targeted, and effective transition metal-based therapies in the nervous system.

Alzheimer's disease (AD), the most prevalent form of dementia, is neuropathologically defined by the accumulation of extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau. Although traditionally viewed as a neuron-centric disorder, increasing evidence underscores the pivotal role of glial cells—particularly microglia and astrocytes—in AD pathogenesis. Once regarded as passive support cells, glia are now recognized as active participants in neuroinflammation, synaptic dysfunction, and disease progression. Microglia, the resident immune cells of the central nervous system, and astrocytes, key regulators of homeostasis and neurotransmission, undergo significant phenotypic changes in response to AD pathology. These include polarization into pro-inflammatory states, impaired clearance of pathological proteins, and detrimental cross talk that amplifies neuroinflammation and neuronal injury. This review synthesizes current literature on the dualistic roles of glial cells in AD, highlighting their contributions to Aβ and tau pathology, synapse loss, demyelination, neurotransmission deficits, and the neuroinflammatory cycle. Emphasis is placed on the dynamic polarization of glia, the reciprocal interactions between microglia and astrocytes, and their combined impact on neurodegeneration. We further explore both pharmacological and non-pharmacological therapeutic approaches targeting glial function, including anti-inflammatory agents, senolytics, deep brain stimulation, exercise, and dietary interventions. By elucidating the multifaceted involvement of glial cells in AD, this review aims to spotlight emerging therapeutic strategies that go beyond neuronal targets, offering new hope for modifying disease progression and improving patient outcomes.