Frontiers in Molecular Neuroscience最新文献

{"title":"Exploring the role of Cdk5 on striatal synaptic plasticity in a 3-NP-induced model of early stages of Huntington's disease.","authors":"Elizabeth Hernández-Echeagaray, Jorge A Miranda-Barrientos, Elizabeth Nieto-Mendoza, Francisco Miguel Torres-Cruz","doi":"10.3389/fnmol.2024.1362365","DOIUrl":"10.3389/fnmol.2024.1362365","url":null,"abstract":"<p><p>Impaired mitochondrial function has been associated with the onset of neurodegenerative diseases. Specifically, certain mitochondrial toxins, such as 3-nitropropionic acid (3-NP), initiate cellular changes within the striatum that closely resemble the pathology observed in Huntington's disease (HD). Among the pivotal signaling molecules contributing to neurodegeneration, cyclin-dependent kinase 5 (Cdk5) stands out. In particular, Cdk5 has been implicated not only in cellular pathology but also in the modulation of synaptic plasticity. Given its widespread presence in the striatum, this study seeks to elucidate the potential role of Cdk5 in the induction of corticostriatal synaptic plasticity in murine striatal cells subjected to subchronic doses of 3-NP <i>in vivo</i>, aiming to mimic the early stages of HD. Immunostaining analyses revealed an increase in Cdk5 in tissues from animals treated with 3-NP, without a significant change in protein levels. Regarding striatal plasticity, long-term depression (LTD) was induced in both control and 3-NP cells when recorded in voltage clamp mode. The Cdk5 inhibitor roscovitine-reduced LTD in most cells. A minority subset of cells exhibited long-term potentiation (LTP) generation in the presence of roscovitine. The inhibitor of D1 receptors SCH23390 prevented LTP in three of nine cells, implying that MSN cells lacking D1/PKA activation were capable of LTP induction when Cdk5 was also blocked. Nevertheless, the co-administration of H89, a PKA inhibitor, along with roscovitine, prevented the generation of any type of plasticity in all recorded cells. These findings show the impact of 3-NP treatment on striatal plasticity and suggest that Cdk5 during early neurodegeneration may attenuate signaling pathways that lead neurons to increase their activity.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1362365"},"PeriodicalIF":3.5,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11576431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681512","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":"Exposure to the antiretroviral drug dolutegravir impairs structure and neurogenesis in a forebrain organoid model of human embryonic cortical development.","authors":"Emma LaNoce, Daniel Y Zhang, Alan Garcia-Epelboim, Yijing Su, Yusha Sun, Giana Alepa, Angelina R Angelucci, Cagla Akay-Espinoza, Kelly L Jordan-Sciutto, Hongjun Song, Guo-Li Ming, Kimberly M Christian","doi":"10.3389/fnmol.2024.1459877","DOIUrl":"10.3389/fnmol.2024.1459877","url":null,"abstract":"<p><strong>Introduction: </strong>For many therapeutic drugs, including antiretroviral drugs used to treat people living with HIV-1 (PLWH), we have little data on the potential effects on the developing human brain due to limited access to tissue and historical constraints on the inclusion of pregnant populations in clinical trials. Human induced pluripotent stem cells (iPSCs) offer a new avenue to gain insight on how drugs may impact human cell types representative of the developing central nervous system. To prevent vertical transmission of HIV and promote the health of pregnant PLWH, antiretroviral therapy must be initiated and/or maintained throughout pregnancy. However, many antiretroviral drugs are approved for widespread use following clinical testing only in non-pregnant populations and there may be limited information on potential teratogenicity until pregnancy outcomes are evaluated. The integrase strand transfer inhibitor dolutegravir (DTG) is a frontline antiretroviral drug that is effective in viral suppression of HIV but was previously reported to be associated with a slight increase in the risk for neural tube defects in one study, although this has not been replicated in other cohorts.</p><p><strong>Methods: </strong>To directly investigate the potential impact of DTG on human cortical neurogenesis, we measured the effects of daily drug exposure on the early stages of corticogenesis in a human iPSC-based forebrain organoid model. We quantified organoid size and structure and analyzed gene and protein expression to evaluate the impact of several doses of DTG on organoid development.</p><p><strong>Results: </strong>We observed deficits in organoid structure and impaired neurogenesis in DTG-treated organoids compared to vehicle-treated control organoids after 20 or 40 days in culture. Our highest dose of DTG (10 μM) resulted in significantly smaller organoids with a reduced density of neural rosette structures compared to vehicle-treated controls. Mechanistically, RNA-sequencing and immunohistological analysis suggests dysregulated amino acid transport and activation of the integrated stress response in the DTG-treated organoids, and functionally, a small molecule integrated stress response inhibitor (ISRIB) could partially rescue increased expression of proteins related to cell cycle regulation.</p><p><strong>Discussion: </strong>Together, these results illustrate the potential for human iPSC-based strategies to reveal biological processes during neurogenesis that may be affected by therapeutic drugs and provide complementary data in relevant human cell types to augment preclinical investigations of drug safety during pregnancy.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1459877"},"PeriodicalIF":3.5,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11576471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681516","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: The role of retinoic acid signaling in maintenance and regeneration of the CNS: from mechanisms to therapeutic targeting.","authors":"Jonathan P T Corcoran, Jörg Mey","doi":"10.3389/fnmol.2024.1491745","DOIUrl":"10.3389/fnmol.2024.1491745","url":null,"abstract":"","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1491745"},"PeriodicalIF":3.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11570587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667727","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":"Spatially resolved transcriptomic signatures of hippocampal subregions and <i>Arc</i>-expressing ensembles in active place avoidance memory.","authors":"Isaac Vingan, Shwetha Phatarpekar, Victoria Sook Keng Tung, Alejandro Iván Hernández, Oleg V Evgrafov, Juan Marcos Alarcon","doi":"10.3389/fnmol.2024.1386239","DOIUrl":"10.3389/fnmol.2024.1386239","url":null,"abstract":"<p><p>The rodent hippocampus is a spatially organized neuronal network that supports the formation of spatial and episodic memories. We conducted bulk RNA sequencing and spatial transcriptomics experiments to measure gene expression changes in the dorsal hippocampus following the recall of active place avoidance (APA) memory. Through bulk RNA sequencing, we examined the gene expression changes following memory recall across the functionally distinct subregions of the dorsal hippocampus. We found that recall induced differentially expressed genes (DEGs) in the CA1 and CA3 hippocampal subregions were enriched with genes involved in synaptic transmission and synaptic plasticity, while DEGs in the dentate gyrus (DG) were enriched with genes involved in energy balance and ribosomal function. Through spatial transcriptomics, we examined gene expression changes following memory recall across an array of spots encompassing putative memory-associated neuronal ensembles marked by the expression of the IEGs <i>Arc</i>, <i>Egr1</i>, and <i>c-Jun</i>. Within samples from both trained and untrained mice, the subpopulations of spatial transcriptomic spots marked by these IEGs were transcriptomically and spatially distinct from one another. DEGs detected between <i>Arc</i> + and <i>Arc</i>- spots exclusively in the trained mouse were enriched in several memory-related gene ontology terms, including \"regulation of synaptic plasticity\" and \"memory.\" Our results suggest that APA memory recall is supported by regionalized transcriptomic profiles separating the CA1 and CA3 from the DG, transcriptionally and spatially distinct IEG expressing spatial transcriptomic spots, and biological processes related to synaptic plasticity as a defining the difference between <i>Arc</i> + and <i>Arc</i>- spatial transcriptomic spots.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1386239"},"PeriodicalIF":3.5,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11560897/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618591","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":"Dissection of signaling pathways regulating TrkB-dependent gephyrin clustering.","authors":"Lisa-Sophie Wüstner, Simone Beuter, Martin Kriebel, Hansjürgen Volkmer","doi":"10.3389/fnmol.2024.1480820","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1480820","url":null,"abstract":"<p><strong>Introduction: </strong>The TrkB receptor is known for its role in regulating excitatory neuronal plasticity. However, accumulating evidence over the past decade has highlighted the involvement of TrkB in regulating inhibitory synapse stability and plasticity, particularly through regulation of the inhibitory scaffold protein gephyrin, although with contradicting results.</p><p><strong>Methods: </strong>In this study, we extended on these findings by overexpressing rat TrkB mutants deficient in either Shc-or PLCγ-dependent signaling, as well as a kinase-dead mutant, to dissect the contributions of specific TrkB-dependent signaling pathways to gephyrin clustering.</p><p><strong>Results: </strong>Our results demonstrate that TrkB signaling is required for gephyrin clustering on the perisomatic area of granule cells in the dentate gyrus <i>in vivo</i>. To further investigate, we expressed TrkB wild-type and mutants in hippocampal neurons <i>in vitro</i>.</p><p><strong>Discussion: </strong>Under basal conditions, TrkB-Shc signaling was important for the reduction of gephyrin cluster size, while TrkB-PLCγ signaling accounts for gephyrin clustering specifically at synaptic sites. Concomitant, impaired PLCγ signaling was associated with disinhibition of transduced neurons. Moreover, chemically induced inhibitory long-term potentiation (chem iLTP) depended on TrkB signaling and the activation of both Shc and PLCγ pathways.</p><p><strong>Conclusion: </strong>Our findings suggest a complex, pathway-specific regulation of TrkB-dependent gephyrin clustering, both under basal conditions and during chem iLTP.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1480820"},"PeriodicalIF":3.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11556255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618579","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":"Spatial transcriptomics analysis identifies therapeutic targets in diffuse high-grade gliomas.","authors":"Yongtao Yang, Yingzhou Hong, Kai Zhao, Minhao Huang, Wenhu Li, Kui Zhang, Ninghui Zhao","doi":"10.3389/fnmol.2024.1466302","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1466302","url":null,"abstract":"<p><strong>Introduction: </strong>Diffuse high-grade gliomas are the most common malignant adult neuroepithelial tumors in humans and a leading cause of cancer-related death worldwide. The advancement of high throughput transcriptome sequencing technology enables rapid and comprehensive acquisition of transcriptome data from target cells or tissues. This technology aids researchers in understanding and identifying critical therapeutic targets for the prognosis and treatment of diffuse high-grade glioma.</p><p><strong>Methods: </strong>Spatial transcriptomics was conducted on two cases of isocitrate dehydrogenase (IDH) wild-type diffuse high-grade glioma (Glio-IDH-wt) and two cases of IDH-mutant diffuse high-grade glioma (Glio-IDH-mut). Gene set enrichment analysis and clustering analysis were employed to pinpoint differentially expressed genes (DEGs) involved in the progression of diffuse high-grade gliomas. The spatial distribution of DEGs in the spatially defined regions of human glioma tissues was overlaid in the t-distributed stochastic neighbor embedding (t-SNE) plots.</p><p><strong>Results: </strong>We identified a total of 10,693 DEGs, with 5,677 upregulated and 5,016 downregulated, in spatially defined regions of diffuse high-grade gliomas. Specifically, <i>SPP1</i>, <i>IGFBP2</i>, <i>CALD1</i>, and <i>TMSB4X</i> exhibited high expression in carcinoma regions of both Glio-IDH-wt and Glio-IDH-mut, and 3 upregulated DEGs (<i>SMOC1</i>, <i>APOE</i>, and <i>HIPK2</i>) and 4 upregulated DEGs (<i>PPP1CB</i>, <i>UBA52</i>, <i>S100A6</i>, and <i>CTSB</i>) were only identified in tumor regions of Glio-IDH-wt and Glio-IDH-mut, respectively. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) enrichment analyses revealed that upregulated DEGs were closely related to PI3K/Akt signaling pathway, virus infection, and cytokine-cytokine receptor interaction. Importantly, the expression of these DEGs was validated using GEPIA databases. Furthermore, the study identified spatial expression patterns of key regulatory genes, including those involved in protein post-translational modification and RNA binding protein-encoding genes, with spatially defined regions of diffuse high-grade glioma.</p><p><strong>Discussion: </strong>Spatial transcriptome analysis is one of the breakthroughs in the field of medical biotechnology as this can map the analytes such as RNA information in their physical location in tissue sections. Our findings illuminate previously unexplored spatial expression profiles of key biomarkers in diffuse high-grade glioma, offering novel insight for the development of therapeutic strategies in glioma.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1466302"},"PeriodicalIF":3.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11552449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618581","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":"Liquid-liquid phase separation and conformational strains of <i>α</i>-Synuclein: implications for Parkinson's disease pathogenesis.","authors":"Eva D Ruiz-Ortega, Anna Wilkaniec, Agata Adamczyk","doi":"10.3389/fnmol.2024.1494218","DOIUrl":"10.3389/fnmol.2024.1494218","url":null,"abstract":"<p><p>Parkinson's disease (PD) and other synucleinopathies are characterized by the aggregation and deposition of alpha-synuclein (<i>α</i>-syn) in brain cells, forming insoluble inclusions such as Lewy bodies (LBs) and Lewy neurites (LNs). The aggregation of <i>α</i>-syn is a complex process involving the structural conversion from its native random coil to well-defined secondary structures rich in <i>β</i>-sheets, forming amyloid-like fibrils. Evidence suggests that intermediate species of <i>α</i>-syn aggregates formed during this conversion are responsible for cell death. However, the molecular events involved in <i>α</i>-syn aggregation and its relationship with disease onset and progression remain not fully elucidated. Additionally, the clinical and pathological heterogeneity observed in various synucleinopathies has been highlighted. Liquid-liquid phase separation (LLPS) and condensate formation have been proposed as alternative mechanisms that could underpin <i>α</i>-syn pathology and contribute to the heterogeneity seen in synucleinopathies. This review focuses on the role of the cellular environment in <i>α</i>-syn conformational rearrangement, which may lead to pathology and the existence of different <i>α</i>-syn conformational strains with varying toxicity patterns. The discussion will include cellular stress, abnormal LLPS formation, and the potential role of LLPS in <i>α</i>-syn pathology.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1494218"},"PeriodicalIF":3.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11537881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142590471","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":"Follicle-stimulating hormone induces depression-like phenotype by affecting synaptic function.","authors":"Liqin Huang, Shangqi Sun, Gege Jiang, Guanfeng Xie, Yunying Yang, Sichun Chen, Jiaying Luo, Chen Lv, Xiang Li, Jianming Liao, Zhihao Wang, Zhaohui Zhang, Jing Xiong","doi":"10.3389/fnmol.2024.1459858","DOIUrl":"10.3389/fnmol.2024.1459858","url":null,"abstract":"<p><p>Depression is one of the most common affective disorders in people's life. Women are susceptibility to depression during puberty, peripartum and menopause transition, when they are suffering from sex hormone fluctuation. A lot of studies have demonstrated the neuroprotective effect of estrogen on depression in women, however, the effect of FSH on depression is unclear. In this study, we investigated the role of FSH on depression in mice. Our study demonstrated that FSH induced depression-like behaviors in mice in a dose-dependent manner. This induction was associated with elevated levels of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-<i>α</i> in both serum and hippocampal tissues. Additionally, FSH treatment resulted in impaired synaptic plasticity and a reduction in the expression of key synaptic proteins. It is noteworthy that the depression-like behaviors, inflammatory cytokines expression and synaptic plasticity impairment induced by FSH could be alleviated by knocking down the expression of FSH receptor (FSHR) in the hippocampus of the mice. Therefore, our findings reveal that FSH may play an important role in the pathogenesis of depression and targeting FSH may be a potential therapeutic strategy for depression during hormone fluctuation in women.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1459858"},"PeriodicalIF":3.5,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11532131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575213","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: Protein post-translational modifications in the nervous system: from development to disease and ageing.","authors":"Beatriz Alvarez, Judit Symmank, Geraldine Zimmer-Bensch, Miguel Diaz-Hernandez, Patricia Franzka","doi":"10.3389/fnmol.2024.1501719","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1501719","url":null,"abstract":"<p><p>PTMs are crucial for biological processes contributing to healthy organ function. Protein post-translational modifications (PTMs), such as phosphorylation (P), acetylation (Ac), SUMOylation (SUMO), S-nitrosylation (Nitro), ubiquitination (Ub) and glycosylation (Glyco), affect a wide range of cellular and biological functions as depicted in this cartoon. Perturbations lead to severe consequences for the normal function of the brain and other organs, such as muscle. Created in BioRender. Hübner (2024) BioRender.com/j49w898.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1501719"},"PeriodicalIF":3.5,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11527776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568282","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: ATF3: a crucial stress-responsive gene of glia and neurons in CNS.","authors":"Ronit Heinrich, Ami Aronheim, Yung-Chih Cheng, Ido Perlman","doi":"10.3389/fnmol.2024.1484487","DOIUrl":"10.3389/fnmol.2024.1484487","url":null,"abstract":"","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"17 ","pages":"1484487"},"PeriodicalIF":3.5,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11525334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557713","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}