Frontiers in Cellular Neuroscience最新文献

{"title":"Impaired olfactory performance and anxiety-like behavior in a rat model of multiple sclerosis are associated with enhanced adenosine signaling in the olfactory bulb via A1R, A2BR, and A3R","authors":"Andjela Stekic, Milorad Dragic, Jelena Stanojevic, Marina Zaric Kontic, Ivana Stevanovic, Milica Zeljkovic Jovanovic, Katarina Mihajlovic, Nadezda Nedeljkovic","doi":"10.3389/fncel.2024.1407975","DOIUrl":"https://doi.org/10.3389/fncel.2024.1407975","url":null,"abstract":"The present study shows that animals with experimental autoimmune encephalomyelitis (EAE) exhibit olfactory dysfunction and impaired general cognitive abilities, as well as anxiety-like behavior. Olfactory dysfunction occurs on average at 2 dpi, well before the onset of the first motor signs of EAE (8–10 dpi). After the initial olfactory dysfunction, the EAE animals show a fluctuation in olfactory performance that resembles the relapsing–remitting course of human MS. The study also shows severe neuroinflammation in the olfactory bulb (OB), with numerous infiltrated CD4<jats:sup>+</jats:sup> T cells and peripheral macrophages in the superficial OB layers, marked microgliosis, and massive induction of TNF-α, IL-1β, and IL-6. Reduced tyrosine hydroxylase activity in the glomerular layer, pronounced granule cell atrophy, and reduced numbers of type B neuroblasts in the rostral migratory stream also indicate altered plasticity of the neuronal network in the OB. Considering the exceptionally high purinome expression in the OB, the possible involvement of purinergic signaling was also investigated. The study shows that macrophages infiltrating the OB overexpress A<jats:sub>3</jats:sub>R, while highly reactive microglia overexpress the adenosine-producing enzyme eN/CD73 as well as A<jats:sub>2B</jats:sub>R, A<jats:sub>3</jats:sub>R, and P2X<jats:sub>4</jats:sub>R. Given the simultaneous induction of complement component C3, the results suggest that the microglial cells develop a functional phenotype of phagocytizing microglia. The study also demonstrates transcriptional and translational upregulation of A<jats:sub>1</jats:sub>R in mitral and tufted cells, which likely influence resting network activity in OB and likely contribute to olfactory dysfunction in EAE. Overall, our study shows that olfactory dysfunction and altered social and cognitive behavior in EAE are associated with increased adenosine signaling via A<jats:sub>1</jats:sub>R, A<jats:sub>2B</jats:sub>R, and A<jats:sub>3</jats:sub>R.","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141873114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potassium channels in animal models of post-traumatic stress disorder: mechanistic and therapeutic implications.","authors":"Ravi Philip Rajkumar","doi":"10.3389/fncel.2024.1441514","DOIUrl":"10.3389/fncel.2024.1441514","url":null,"abstract":"","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11319181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975513","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":"Frontiers | Potential role of endothelial progenitor cells in the pathogenesis and treatment of cerebral aneurysm","authors":"Jin Yu, Qian Du, Xiang Li, Wei Wei, Yuncun Fan, Jianjian Zhang, Jincao Chen","doi":"10.3389/fncel.2024.1456775","DOIUrl":"https://doi.org/10.3389/fncel.2024.1456775","url":null,"abstract":"Cerebral aneurysm (CA) is a significant health concern that results from pathological dilations of blood vessels in the brain and can lead to severe and potentially life-threatening conditions. While the pathogenesis of CA is complex, emerging studies suggest that endothelial progenitor cells (EPCs) play a crucial role. In this paper, we conducted a comprehensive literature review to investigate the potential role of EPCs in the pathogenesis and treatment of CA. Current research indicates that a decreased count and dysfunction of EPCs disrupt the balance between endothelial dysfunction and repair, thus increasing the risk of CA formation. Reversing these EPCs abnormalities may reduce the progression of vascular degeneration after aneurysm induction, indicating EPCs as a promising target for developing new therapeutic strategies to facilitate CA repair. This has motivated researchers to develop novel treatment options, including drug applications, endovascular-combined and tissue engineering therapies. Although preclinical studies have shown promising results, there is still a considerable way to go before clinical translation and eventual benefits for patients. Nonetheless, these findings offer hope for improving the treatment and management of this condition.","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141931156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel autism-associated KCNB1 mutation dramatically slows Kv2.1 potassium channel activation, deactivation and inactivation","authors":"Rían W. Manville, Samantha D. Block, Claire L. Illeck, Jessica Kottmeier, Richard Sidlow, Geoffrey W. Abbott","doi":"10.3389/fncel.2024.1438101","DOIUrl":"https://doi.org/10.3389/fncel.2024.1438101","url":null,"abstract":"<jats:italic>KCNB1</jats:italic>, on human chromosome 20q13.3, encodes the alpha subunit of the Kv2.1 voltage gated potassium channel. Kv2.1 is ubiquitously expressed throughout the brain and is critical in controlling neuronal excitability, including in the hippocampus and pyramidal neurons. Human <jats:italic>KCNB1</jats:italic> mutations are known to cause global development delay or plateauing, epilepsy, and behavioral disorders. Here, we report a sibling pair with developmental delay, absence seizures, autism spectrum disorder, hypotonia, and dysmorphic features. Whole exome sequencing revealed a heterozygous variant of uncertain significance (c. 342 C&amp;gt;A), p. (S114R) in <jats:italic>KCNB1</jats:italic>, encoding a serine to arginine substitution (S114R) in the N-terminal cytoplasmic region of Kv2.1. The siblings’ father demonstrated autistic features and was determined to be an obligate <jats:italic>KCNB1</jats:italic> c. 342 C&amp;gt;A carrier based on familial genetic testing results. Functional investigation of Kv2.1-S114R using cellular electrophysiology revealed slowing of channel activation, deactivation, and inactivation, resulting in increased net current after longer membrane depolarizations. To our knowledge, this is the first study of its kind that compares the presentation of siblings each with a <jats:italic>KCNB1</jats:italic> disorder. Our study demonstrates that Kv2.1-S114R has profound cellular and phenotypic consequences. Understanding the mechanisms underlying <jats:italic>KCNB1</jats:italic>-linked disorders aids clinicians in diagnosis and treatment and provides potential therapeutic avenues to pursue.","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141869133","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroinflammation in Parkinson’s disease: focus on the relationship between miRNAs and microglia","authors":"Ke Xu, Yuan Li, Yan Zhou, Yu Zhang, Yue Shi, Chengguang Zhang, Yan Bai, Shun Wang","doi":"10.3389/fncel.2024.1429977","DOIUrl":"https://doi.org/10.3389/fncel.2024.1429977","url":null,"abstract":"Parkinson’s disease (PD) is a prevalent neurodegenerative disorder that affects the central nervous system (CNS). Neuroinflammation is a crucial factor in the pathological advancement of PD. PD is characterized by the presence of activated microglia and increased levels of proinflammatory factors, which play a crucial role in its pathology. During the immune response of PD, microglia regulation is significantly influenced by microRNA (miRNA). The excessive activation of microglia, persistent neuroinflammation, and abnormal polarization of macrophages in the brain can be attributed to the dysregulation of certain miRNAs. Additionally, there are miRNAs that possess the ability to inhibit neuroinflammation. miRNAs, which are small non-coding epigenetic regulators, have the ability to modulate microglial activity in both normal and abnormal conditions. They also have a significant impact on promoting communication between neurons and microglia.","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141772122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A decrease in Fkbp52 alters autophagosome maturation and A152T-tau clearance in vivo","authors":"Emilie Lesport, Lucie Commeau, Mélanie Genet, Etienne-Emile Baulieu, Marcel Tawk, Julien Giustiniani","doi":"10.3389/fncel.2024.1425222","DOIUrl":"https://doi.org/10.3389/fncel.2024.1425222","url":null,"abstract":"The failure of the autophagy-lysosomal pathway to clear the pathogenic forms of Tau exacerbates the pathogenesis of tauopathies. We have previously shown that the immunophilin FKBP52 interacts both physically and functionally with Tau, and that a decrease in FKBP52 protein levels is associated with Tau deposition in affected human brains. We have also shown that FKBP52 is physiologically present within the lysosomal system in healthy human neurons and that a decrease in FKBP52 expression alters perinuclear lysosomal positioning and Tau clearance during Tau-induced proteotoxic stress <jats:italic>in vitro</jats:italic>. In this study, we generate a zebrafish <jats:italic>fkbp4</jats:italic> loss of function mutant and show that axonal retrograde trafficking of Lamp1 vesicles is altered in this mutant. Moreover, using our transgenic <jats:italic>HuC::mCherry-EGFP-LC3</jats:italic> line, we demonstrate that the autophagic flux is impaired in <jats:italic>fkbp4</jats:italic> mutant embryos, suggesting a role for Fkbp52 in the maturation of autophagic vesicles. Alterations in both axonal transport and autophagic flux are more evident in heterozygous rather than homozygous <jats:italic>fkbp4</jats:italic> mutants. Finally, taking advantage of the previously described A152T-Tau transgenic fish, we show that the clearance of pathogenic A152T-Tau mutant proteins is slower in <jats:italic>fkbp4</jats:italic><jats:sup>+/−</jats:sup> mutants in comparison to <jats:italic>fkbp4</jats:italic><jats:sup>+/+</jats:sup> larvae. Altogether, these results indicate that Fkbp52 is required for the normal trafficking and maturation of lysosomes and autophagic vacuoles along axons, and that its decrease is sufficient to hinder the clearance of pathogenic Tau <jats:italic>in vivo</jats:italic>.","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141772123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling riboflavin transporter deficiency type 2: from iPSC-derived motoneurons to iPSC-derived astrocytes","authors":"Valentina Magliocca, Angela Lanciotti, Elena Ambrosini, Lorena Travaglini, Veronica D’Ezio, Valentina D’Oria, Stefania Petrini, Michela Catteruccia, Keith Massey, Marco Tartaglia, Enrico Bertini, Tiziana Persichini, Claudia Compagnucci","doi":"10.3389/fncel.2024.1440555","DOIUrl":"https://doi.org/10.3389/fncel.2024.1440555","url":null,"abstract":"IntroductionRiboflavin transporter deficiency type 2 (RTD2) is a rare neurodegenerative autosomal recessive disease caused by mutations in the SLC52A2 gene encoding the riboflavin transporters, RFVT2. Riboflavin (Rf) is the precursor of FAD (flavin adenine dinucleotide) and FMN (flavin mononucleotide), which are involved in different redox reactions, including the energetic metabolism processes occurring in mitochondria. To date, human induced pluripotent stem cells (iPSCs) have given the opportunity to characterize RTD2 motoneurons, which reflect the most affected cell type. Previous works have demonstrated mitochondrial and peroxisomal altered energy metabolism as well as cytoskeletal derangement in RTD2 iPSCs and iPSC-derived motoneurons. So far, no attention has been dedicated to astrocytes.Results and discussionHere, we demonstrate that <jats:italic>in vitro</jats:italic> differentiation of astrocytes, which guarantee trophic and metabolic support to neurons, from RTD2 iPSCs is not compromised. These cells do not exhibit evident morphological differences nor significant changes in the survival rate when compared to astrocytes derived from iPSCs of healthy individuals. These findings indicate that differently from what had previously been documented for neurons, RTD2 does not compromise the morpho-functional features of astrocytes.","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141772233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic approaches to elucidating cortical and hippocampal GABAergic interneuron diversity","authors":"Robert Machold, Bernardo Rudy","doi":"10.3389/fncel.2024.1414955","DOIUrl":"https://doi.org/10.3389/fncel.2024.1414955","url":null,"abstract":"GABAergic interneurons (INs) in the mammalian forebrain represent a diverse population of cells that provide specialized forms of local inhibition to regulate neural circuit activity. Over the last few decades, the development of a palette of genetic tools along with the generation of single-cell transcriptomic data has begun to reveal the molecular basis of IN diversity, thereby providing deep insights into how different IN subtypes function in the forebrain. In this review, we outline the emerging picture of cortical and hippocampal IN speciation as defined by transcriptomics and developmental origin and summarize the genetic strategies that have been utilized to target specific IN subtypes, along with the technical considerations inherent to each approach. Collectively, these methods have greatly facilitated our understanding of how IN subtypes regulate forebrain circuitry via cell type and compartment-specific inhibition and thus have illuminated a path toward potential therapeutic interventions for a variety of neurocognitive disorders.","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141772124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oligodendrocyte precursor cell-derived exosomes combined with cell therapy promote clinical recovery by immunomodulation and gliosis attenuation","authors":"Sarah Ingrid Pinto Santos, Santiago José Ortiz-Peñuela, Alessandro de Paula Filho, Ana Laura Midori Rossi Tomiyama, Lilian de Oliveira Coser, Juliano Coelho da Silveira, Daniele dos Santos Martins, Adriano Polican Ciena, Alexandre Leite Rodrigues de Oliveira, Carlos Eduardo Ambrósio","doi":"10.3389/fncel.2024.1413843","DOIUrl":"https://doi.org/10.3389/fncel.2024.1413843","url":null,"abstract":"Multiple sclerosis is a chronic inflammatory disease of the central nervous system characterized by autoimmune destruction of the myelin sheath, leading to irreversible and progressive functional deficits in patients. Pre-clinical studies involving the use of neural stem cells (NSCs) have already demonstrated their potential in neuronal regeneration and remyelination. However, the exclusive application of cell therapy has not proved sufficient to achieve satisfactory therapeutic levels. Recognizing these limitations, there is a need to combine cell therapy with other adjuvant protocols. In this context, extracellular vesicles (EVs) can contribute to intercellular communication, stimulating the production of proteins and lipids associated with remyelination and providing trophic support to axons. This study aimed to evaluate the therapeutic efficacy of the combination of NSCs and EVs derived from oligodendrocyte precursor cells (OPCs) in an animal model of multiple sclerosis. OPCs were differentiated from NSCs and had their identity confirmed by gene expression analysis and immunocytochemistry. Exosomes were isolated by differential ultracentrifugation and characterized by Western, transmission electron microscopy and nanoparticle tracking analysis. Experimental therapy of C57BL/6 mice induced with experimental autoimmune encephalomyelitis (EAE) were grouped in control, treated with NSCs, treated with OPC-derived EVs and treated with a combination of both. The treatments were evaluated clinically using scores and body weight, microscopically using immunohistochemistry and immunological profile by flow cytometry. The animals showed significant clinical improvement and weight gain with the treatments. However, only the treatments involving EVs led to immune modulation, changing the profile from Th1 to Th2 lymphocytes. Fifteen days after treatment revealed a reduction in reactive microgliosis and astrogliosis in the groups treated with EVs. However, there was no reduction in demyelination. The results indicate the potential therapeutic use of OPC-derived EVs to attenuate inflammation and promote recovery in EAE, especially when combined with cell therapy.","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141772126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel histone deacetylase inhibitor W2A-16 improves the barrier integrity in brain vascular endothelial cells","authors":"Yasuteru Inoue, Yingxue Ren, Shuwen Zhang, Michael Bamkole, Naeyma N. Islam, Manikandan Selvaraj, Wenyan Lu, Thomas R. Caulfield, Yonghe Li, Takahisa Kanekiyo","doi":"10.3389/fncel.2024.1368018","DOIUrl":"https://doi.org/10.3389/fncel.2024.1368018","url":null,"abstract":"The maturation of brain microvascular endothelial cells leads to the formation of a tightly sealed monolayer, known as the blood–brain barrier (BBB). The BBB damage is associated with the pathogenesis of age-related neurodegenerative diseases including vascular cognitive impairment and Alzheimer’s disease. Growing knowledge in the field of epigenetics can enhance the understanding of molecular profile of the BBB and has great potential for the development of novel therapeutic strategies or targets to repair a disrupted BBB. Histone deacetylases (HDACs) inhibitors are epigenetic regulators that can induce acetylation of histones and induce open chromatin conformation, promoting gene expression by enhancing the binding of DNA with transcription factors. We investigated how HDAC inhibition influences the barrier integrity using immortalized human endothelial cells (HCMEC/D3) and the human induced pluripotent stem cell (iPSC)-derived brain vascular endothelial cells. The endothelial cells were treated with or without a novel compound named W2A-16. W2A-16 not only activates Wnt/β-catenin signaling but also functions as a class I HDAC inhibitor. We demonstrated that the administration with W2A-16 sustained barrier properties of the monolayer of endothelial cells, as evidenced by increased trans-endothelial electrical resistance (TEER). The BBB-related genes and protein expression were also increased compared with non-treated controls. Analysis of transcript profiles through RNA-sequencing in hCMEC/D3 cells indicated that W2A-16 potentially enhances BBB integrity by influencing genes associated with the regulation of the extracellular microenvironment. These findings collectively propose that the HDAC inhibition by W2A-16 plays a facilitating role in the formation of the BBB. Pharmacological approaches to inhibit HDAC may be a potential therapeutic strategy to boost and/or restore BBB integrity.","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141744313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}