Frontiers in Molecular Neuroscience最新文献

{"title":"Deciphering motor dysfunction and microglial activation in mThy1-<i>α</i>-synuclein mice: a comprehensive study of behavioral, gene expression, and methylation changes.","authors":"Brett A McGregor, Md Obayed Raihan, Afrina Brishti, Junguk Hur, James E Porter","doi":"10.3389/fnmol.2025.1544971","DOIUrl":"10.3389/fnmol.2025.1544971","url":null,"abstract":"<p><strong>Introduction: </strong>Growing recognition of microglia's role in neurodegenerative disorders has accentuated the need to characterize microglia profiles and their influence on pathogenesis. To understand changes observed in the microglial profile during the progression of synucleinopathies, microglial gene expression and DNA methylation were examined in the mThy1-<i>α</i>-synuclein mouse model.</p><p><strong>Methods: </strong>Disease progression was determined using behavioral tests evaluating locomotor deficits before DNA and RNA extraction at 7 and 10 months from isolated microglia for enzymatic methyl-sequencing and RNA-sequencing.</p><p><strong>Results: </strong>Pathway analysis of these changes at 7 months indicates a pro-inflammatory profile and changes in terms related to synaptic maintenance. Expression and methylation at both 7 and 10 months included terms regarding mitochondrial and metabolic stress. While behavior symptoms progressed at 10 months, we see many previously activated pathways being inhibited in microglia at a later stage, with only 8 of 53 shared pathways predicted to be directionally concordant. Despite the difference in pathway directionality, 21 of the 22 genes that were differentially expressed and annotated to differentially methylated regions at both 7 and 10 months had conserved directionality changes.</p><p><strong>Discussion: </strong>These results highlight a critical period in disease progression, during which the microglia respond to <i>α</i>-synuclein, suggesting a transition in the role of microglia from the early to late stages of the disease.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1544971"},"PeriodicalIF":3.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11865073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The emerging role of glycine receptor α2 subunit defects in neurodevelopmental disorders.","authors":"Sean D Fraser, Robert J Harvey","doi":"10.3389/fnmol.2025.1550863","DOIUrl":"10.3389/fnmol.2025.1550863","url":null,"abstract":"<p><p>Rare neurodevelopmental disorders (NDDs) are one of the most significant unmet challenges in healthcare due to their lifelong nature, high management costs, and recurrence within families. This review will focus on newly-emerging genetic forms of NDDs resulting from variants in the glycine receptor (GlyR) α2 subunit gene. Studies using <i>Glra2</i> knockout mice have convincingly demonstrated that GlyR α2 is essential for cortical interneuron migration and progenitor homeostasis. Genetic inactivation of GlyR α2 impairs the capacity of apical progenitors to generate basal progenitors, resulting in an overall reduction of projection neurons in the cerebral cortex. As a result, microcephaly is observed in newborn <i>Glra2</i> knockout mice, as well as defects in neuronal morphology, increased susceptibility to seizures, and defects in novel object recognition, motor memory consolidation, righting reflexes, novelty-induced locomotion in the open field test, and motivational reward tasks. Consistent with these findings, we and others have identified missense variants and microdeletions in the human GlyR α2 subunit gene (<i>GLRA2</i>) in individuals with autism spectrum disorder (ASD), developmental delay (DD) and/or intellectual disability (ID), often accompanied by microcephaly, language delay and epilepsy. In this review, we highlight the critical role of the GlyR α2 subunit revealed by knockout mice and our current understanding of GlyR α2 pathomechanisms in human NDDs. Finally, we will consider the current gaps in our knowledge, which include: (i) Limited functional validation for GlyR α2 missense variants associated with human NDDs; (ii) The lack of <i>gain-of-function</i> GlyR α2 mouse models; (iii) Our limited knowledge of GlyR α2 interacting proteins. We also highlight potential future developments in the field, including routes to personalized medicines for individuals with GlyR α2 mutations.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1550863"},"PeriodicalIF":3.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11850347/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143500559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Spatio-temporal molecular mechanisms regulating synapse function and neural circuit dynamics.","authors":"Tomohisa Hosokawa, Yoshiyuki Kubota, Tetsuya Takano","doi":"10.3389/fnmol.2025.1564028","DOIUrl":"https://doi.org/10.3389/fnmol.2025.1564028","url":null,"abstract":"","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1564028"},"PeriodicalIF":3.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11842370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Latest advances in neuroscience at the 9th Croatian Neuroscience Congress.","authors":"Kristina Mlinac-Jerkovic, Marija Heffer, Svjetlana Kalanj-Bognar, Senka Blažetić","doi":"10.3389/fnmol.2025.1563899","DOIUrl":"10.3389/fnmol.2025.1563899","url":null,"abstract":"","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1563899"},"PeriodicalIF":3.5,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11839593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143467731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPCRs in hypothalamic neurons and their roles in controlling food intake and metabolism.","authors":"Tian Qiu, Ou Fu","doi":"10.3389/fnmol.2025.1536577","DOIUrl":"10.3389/fnmol.2025.1536577","url":null,"abstract":"<p><p>G-protein coupled receptor (GPCR) subtypes within the hypothalamus play a pivotal role in maintaining body homeostasis, particularly in the regulation of food intake and energy metabolism. This review provides an overview of classical loss and gain-of-function studies on GPCRs related to feeding and metabolism, with a focus on emerging cell-type-specific investigations. These studies reveal that diverse GPCR-expressing neuronal populations are intricately linked to feeding and energy balance. We also discuss recent findings that highlight the interaction of distinct peptide-GPCR systems in modulating complex feeding behaviors.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1536577"},"PeriodicalIF":3.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11835808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effect of AKT inhibition in α-synuclein-dependent neurodegeneration.","authors":"Bedri Ranxhi, Zoya R Bangash, Zachary M Chbihi, Sokol V Todi, Peter A LeWitt, Wei-Ling Tsou","doi":"10.3389/fnmol.2025.1524044","DOIUrl":"10.3389/fnmol.2025.1524044","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting millions of individuals worldwide. A hallmark of PD pathology is the accumulation of α-synuclein (α-Syn), a small protein known to support neuronal development and function. However, in PD, α-Syn cumulatively misfolds into toxic aggregates that disrupt cellular processes and contribute to neuronal damage and neurodegeneration. Previous studies implicated the AKT signaling pathway in α-Syn toxicity in cellular models of PD, suggesting AKT as a potential therapeutic target. Here, we investigated the effect of AKT inhibition in a <i>Drosophila</i> model of synucleinopathy. We observed that administration of the AKT inhibitor, A-443654 led to mild improvements in both survival and motor function in flies expressing human α-Syn. Genetic studies revealed that reduction of AKT levels decreased α-Syn protein levels, concomitant with improved physiological outcomes. The protective effects of AKT reduction appear to operate through the fly ortholog of NF-κB, Relish, suggesting a link between AKT and NF-κB in regulating α-Syn levels. These findings highlight the AKT cascade as a potential therapeutic target for synucleinopathies and provide insights into mechanisms that could be utilized to reduce α-Syn toxicity in PD and related disorders, such as multiple system atrophy.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1524044"},"PeriodicalIF":3.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11835820/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ectopic expression of the cation-chloride cotransporter KCC2 in blood exosomes as a biomarker for functional rehabilitation.","authors":"L Caccialupi Da Prato, A Rezzag Lebza, A Consumi, M Tessier, A Srinivasan, C Rivera, J Laurin, C Pellegrino","doi":"10.3389/fnmol.2025.1522571","DOIUrl":"10.3389/fnmol.2025.1522571","url":null,"abstract":"<p><strong>Background: </strong>Traumatic brain injury (TBI) is a major cause of disabilities in industrialized countries. Cognitive decline typically occurs in the chronic phase of the condition, following cellular and molecular processes. In this study, we described the use of KCC2, a neuronal-specific potassium-chloride cotransporter, as a potent biomarker to predict cognitive dysfunction after TBI.</p><p><strong>Methods: </strong>Using neuronal and total exosome collections from the blood serum of the controls and patients with TBI, we were able to anticipate the decline in cognitive performance.</p><p><strong>Results: </strong>After TBI, we observed a significant and persistent loss of KCC2 expression in the blood exosomes, which was correlated with the changes in the network activity and cellular processes such as secondary neurogenesis. Furthermore, we established a correlation between this decrease in KCC2 expression and the long-term consequences of brain trauma and identified a link between the loss of KCC2 expression and the emergence of depressive-like behavior observed in the mice.</p><p><strong>Conclusion: </strong>We successfully validated our previous findings, supporting the potential therapeutic benefits of bumetanide in mitigating post-traumatic depression (PTD) following TBI. This effect was correlated with the recovery of KCC2 expression in the blood exosomes, the prevention of extensive neuronal loss among the interneurons, and changes in secondary neurogenesis.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1522571"},"PeriodicalIF":3.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11835807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143457688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Nervous regeneration and functional recovery in the central and peripheral nervous systems: diagnostic methods, gene/cell therapies, and interventions.","authors":"Dipa Natarajan, Ryo Hotta, Naho Fujiwara, Silvia Perin","doi":"10.3389/fnmol.2025.1555390","DOIUrl":"https://doi.org/10.3389/fnmol.2025.1555390","url":null,"abstract":"","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1555390"},"PeriodicalIF":3.5,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11832513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinicopathological and molecular characterization of astrocytoma.","authors":"Xiaoyan Wu, Wenfeng Peng, Xu Zhang, Tao Tang, Ling Deng, Yuxia Xu, Xiaoyun Liu, Fang Wang, Wujian Peng, Jianrong Huang, Xiaoni Zhong","doi":"10.3389/fnmol.2025.1483833","DOIUrl":"10.3389/fnmol.2025.1483833","url":null,"abstract":"<p><strong>Introduction: </strong>Astrocytoma is a rare tumour of the central nervous system that often manifests with non-specific clinical symptoms and lacks distinct histological features. There is a pressing need for further understanding of the clinicopathological and molecular characteristics of astrocytoma. Identifying mutant genes can aid in reliable and early diagnosis, as well as provide insights for the development of targeted therapies.</p><p><strong>Methods: </strong>This study aims to investigate the clinicopathologic and molecular characteristics of astroblastoma. A total of four patients diagnosed with astroblastoma were included in the analysis. Clinical features, histological findings, and immunohistochemistry results were reviewed and analyzed. Genetic alterations were identified using fluorescence <i>in situ</i> hybridization (FISH) and next-generation sequencing (NGS), followed by patient follow-up.</p><p><strong>Results: </strong>The study included four female patients, ranging in age from 8 to 44 years. One patient had a tumour in the right parietal lobe, while the other three had tumours in the spinal cord. Histology is usually characterized by pseudorosettes of astroblasts and hyalinization of blood vessels. These tumors showed a growth pattern similar to traditional intracranial astroblastoma, and the histological manifestations of the four patients were all high-grade, showing features of high-density areas of tumor cells or necrosis. Immunohistochemical staining revealed that all four patients expressed OLIG2, EMA, and vimentin, while three patients also expressed GFAP and S-100. The Ki-67 positivity index was approximately 15% in three cases and 10% in one case. Fluorescence <i>in situ</i> hybridization (FISH) using break-apart probes showed EWRS1 breaks in three patients and MN1 breaks in one. Further DNA or RNA-targeted biallelic sequencing identified an EWSR1(Exon1-7)-BEND2(Exon2-14) fusion in case 1, and an EWSR1(Exon1-7)-BEND2(Intergenic) fusion in case 2. In case 3, an EWSR1(Exon1-7)-NUDT10(Intergenic) fusion was present, and in case 4, an MN1(Exon1)-BEND2(Exon2) fusion was identified. The EWSR1-NUDT10 gene fusion is a new fusion type in astroblastoma. The patients were followed up for 76.5, 17.6, 33.7, and 61.3 months, respectively. Three cases experienced tumour recurrences at the spinal cord site, with multiple recurrences in case 4.</p><p><strong>Discussion: </strong>Our study unveiled the distinctive clinicopathological and molecular mutational characteristics of astrocytoma, while also identifying rare mutated genes. Additionally, the detection of MN1 or EWSR1 gene fusion through FISH or next-generation sequencing can provide valuable insights into the molecular mechanisms and aid in the differential diagnosis of astrocytoma.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1483833"},"PeriodicalIF":3.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11830656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired peroxisomal beta-oxidation in microglia triggers oxidative stress and impacts neurons and oligodendrocytes.","authors":"Ali Tawbeh, Catherine Gondcaille, Fatima-Ezzahra Saih, Quentin Raas, Damien Loichot, Yannick Hamon, Céline Keime, Alexandre Benani, Francesca Di Cara, Mustapha Cherkaoui-Malki, Pierre Andreoletti, Stéphane Savary","doi":"10.3389/fnmol.2025.1542938","DOIUrl":"10.3389/fnmol.2025.1542938","url":null,"abstract":"<p><p>Microglia, the immune cells of the central nervous system, activate neuroinflammatory pathways in response to homeostatic disturbances, a process implicated in the pathogenesis of various neurodegenerative diseases. Emerging evidence identifies abnormal microglial activation as a causal factor at the onset of peroxisomal leukodystrophies, including X-linked adrenoleukodystrophy (X-ALD). This study investigates how primary peroxisomal deficiencies influence oxidative properties of microglia and examines the subsequent impact on neurons and oligodendrocytes. Using BV-2 microglial cells lacking ABCD1, ABCD2, or ACOX1, peroxisomal proteins that play key roles in the very-long-chain fatty acid beta-oxidation, we analyzed their response under basal condition and after stimulation by lipopolysaccharide (LPS). Transcriptomic analysis of the mutant microglial cells revealed numerous differentially expressed genes, particularly in redox-related pathways following LPS exposure. These changes are consistent with the increased production of reactive oxygen species (ROS) and nitric oxide (NO). Conditioned media (CM) from the mutant cells were then applied to cultures of neuron and oligodendrocyte cell lines. Exposure to CM from LPS-stimulated mutant microglial cells significantly increased apoptosis in both cell types. Furthermore, treated neurons exhibited a reduction in cell complexity and an increased ability to secrete neuropeptides. These findings demonstrate that peroxisomal impairments in microglia exacerbate inflammatory response and ROS/NO production, affecting the survival of neurons and oligodendrocytes, as well as neuronal morphology and function. This dysfunction might contribute to the early neurodegenerative events in X-ALD by triggering and sustaining neuroinflammatory cascades. Therapeutic strategies that target microglial activation and secretion profiles could hold promise in managing peroxisomal disorders such as X-ALD.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1542938"},"PeriodicalIF":3.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11826809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}