Pub Date : 2024-05-22DOI: 10.3389/fnmol.2024.1389100
Emily R Brocato, Rachel Easter, Alanna Morgan, Meenakshi Kakani, Grace Lee, Jennifer T. Wolstenholme
Binge drinking in adolescence can disrupt myelination and cause brain structural changes that persist into adulthood. Alcohol consumption at a younger age increases the susceptibility of these changes. Animal models to understand ethanol’s actions on myelin and white matter show that adolescent binge ethanol can alter the developmental trajectory of oligodendrocytes, myelin structure, and myelin fiber density. Oligodendrocyte differentiation is epigenetically regulated by H3K9 trimethylation (H3K9me3). Prior studies have shown that adolescent binge ethanol dysregulates H3K9 methylation and decreases H3K9-related gene expression in the PFC.Here, we assessed ethanol-induced changes to H3K9me3 occupancy at genomic loci in the developing adolescent PFC. We further assessed ethanol-induced changes at the transcription level with qPCR time course approaches in oligodendrocyte-enriched cells to assess changes in oligodendrocyte progenitor and oligodendrocytes specifically.Adolescent binge ethanol altered H3K9me3 regulation of synaptic-related genes and genes specific for glutamate and potassium channels in a sex-specific manner. In PFC tissue, we found an early change in gene expression in transcription factors associated with oligodendrocyte differentiation that may lead to the later significant decrease in myelin-related gene expression. This effect appeared stronger in males.Further exploration in oligodendrocyte cell enrichment time course and dose response studies could suggest lasting dysregulation of oligodendrocyte maturation at the transcriptional level. Overall, these studies suggest that binge ethanol may impede oligodendrocyte differentiation required for ongoing myelin development in the PFC by altering H3K9me3 occupancy at synaptic-related genes. We identify potential genes that may be contributing to adolescent binge ethanol-related myelin loss.
{"title":"Adolescent binge ethanol impacts H3K9me3-occupancy at synaptic genes and the regulation of oligodendrocyte development","authors":"Emily R Brocato, Rachel Easter, Alanna Morgan, Meenakshi Kakani, Grace Lee, Jennifer T. Wolstenholme","doi":"10.3389/fnmol.2024.1389100","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1389100","url":null,"abstract":"Binge drinking in adolescence can disrupt myelination and cause brain structural changes that persist into adulthood. Alcohol consumption at a younger age increases the susceptibility of these changes. Animal models to understand ethanol’s actions on myelin and white matter show that adolescent binge ethanol can alter the developmental trajectory of oligodendrocytes, myelin structure, and myelin fiber density. Oligodendrocyte differentiation is epigenetically regulated by H3K9 trimethylation (H3K9me3). Prior studies have shown that adolescent binge ethanol dysregulates H3K9 methylation and decreases H3K9-related gene expression in the PFC.Here, we assessed ethanol-induced changes to H3K9me3 occupancy at genomic loci in the developing adolescent PFC. We further assessed ethanol-induced changes at the transcription level with qPCR time course approaches in oligodendrocyte-enriched cells to assess changes in oligodendrocyte progenitor and oligodendrocytes specifically.Adolescent binge ethanol altered H3K9me3 regulation of synaptic-related genes and genes specific for glutamate and potassium channels in a sex-specific manner. In PFC tissue, we found an early change in gene expression in transcription factors associated with oligodendrocyte differentiation that may lead to the later significant decrease in myelin-related gene expression. This effect appeared stronger in males.Further exploration in oligodendrocyte cell enrichment time course and dose response studies could suggest lasting dysregulation of oligodendrocyte maturation at the transcriptional level. Overall, these studies suggest that binge ethanol may impede oligodendrocyte differentiation required for ongoing myelin development in the PFC by altering H3K9me3 occupancy at synaptic-related genes. We identify potential genes that may be contributing to adolescent binge ethanol-related myelin loss.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141109918","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}
Multiple sclerosis (MS) is an immune-mediated disease characterized by inflammatory demyelinating lesions in the central nervous system. Studies have shown that the inflammation is vital to both the onset and progression of MS, where aging plays a key role in it. However, the potential mechanisms on how aging-related inflammation (inflammaging) promotes MS have not been fully understood. Therefore, there is an urgent need to integrate the underlying mechanisms between inflammaging and MS, where meaningful prediction models are needed.First, both aging and disease models were developed using machine learning methods, respectively. Then, an integrated inflammaging model was used to identify relative risk factors, by identifying essential “aging-inflammation-disease” triples. Finally, a series of bioinformatics analyses (including network analysis, enrichment analysis, sensitivity analysis, and pan-cancer analysis) were further used to explore the potential mechanisms between inflammaging and MS.A series of risk factors were identified, such as the protein homeostasis, cellular homeostasis, neurodevelopment and energy metabolism. The inflammaging indices were further validated in different cancer types. Therefore, various risk factors were integrated, and even both the theories of inflammaging and immunosenescence were further confirmed.In conclusion, our study systematically investigated the potential relationships between inflammaging and MS through a series of computational approaches, and could present a novel thought for other aging-related diseases.
{"title":"Identification of crucial inflammaging related risk factors in multiple sclerosis","authors":"Mengchu Xu, Huize Wang, Siwei Ren, Bing Wang, Wenyan Yang, Ling Lv, Xianzheng Sha, Wenya Li, Yin Wang","doi":"10.3389/fnmol.2024.1398665","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1398665","url":null,"abstract":"Multiple sclerosis (MS) is an immune-mediated disease characterized by inflammatory demyelinating lesions in the central nervous system. Studies have shown that the inflammation is vital to both the onset and progression of MS, where aging plays a key role in it. However, the potential mechanisms on how aging-related inflammation (inflammaging) promotes MS have not been fully understood. Therefore, there is an urgent need to integrate the underlying mechanisms between inflammaging and MS, where meaningful prediction models are needed.First, both aging and disease models were developed using machine learning methods, respectively. Then, an integrated inflammaging model was used to identify relative risk factors, by identifying essential “aging-inflammation-disease” triples. Finally, a series of bioinformatics analyses (including network analysis, enrichment analysis, sensitivity analysis, and pan-cancer analysis) were further used to explore the potential mechanisms between inflammaging and MS.A series of risk factors were identified, such as the protein homeostasis, cellular homeostasis, neurodevelopment and energy metabolism. The inflammaging indices were further validated in different cancer types. Therefore, various risk factors were integrated, and even both the theories of inflammaging and immunosenescence were further confirmed.In conclusion, our study systematically investigated the potential relationships between inflammaging and MS through a series of computational approaches, and could present a novel thought for other aging-related diseases.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141114733","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}
Zinc transporter 3 (ZnT3) is abundantly expressed in the brain, residing in synaptic vesicles, where it plays important roles in controlling the luminal zinc levels. In this study, we found that ZnT3 knockout in mice decreased zinc levels in the hippocampus and cortex, and was associated with progressive cognitive impairments, assessed at 2, 6, and 9-month of age. The results of Golgi-Cox staining demonstrated that ZnT3 deficiency was associated with an increase in dendritic complexity and a decrease in the density of mature dendritic spines, indicating potential synaptic plasticity deficit. Since ZnT3 deficiency was previously linked to glucose metabolism abnormalities, we tested the expression levels of genes related to insulin signaling pathway in the hippocampus and cortex. We found that the Expression of glucose transporters, GLUT3, GLUT4, and the insulin receptor in the whole tissue and synaptosome fraction of the hippocampus of the ZnT3 knockout mice were significantly reduced, as compared to wild-type controls. Expression of AKT (A serine/threonine protein kinase) and insulin-induced AKT phosphorylation was also reduced in the hippocampus of ZnT3 knockout mice. We hypothesize that the ZnT3 deficiency and reduced brain zinc levels may cause cognitive impairment by negatively affecting glycose metabolism via decreased expression of key components of insulin signaling, as well as via changes in synaptic plasticity. These finding may provide new therapeutic target for treatments of neurodegenerative disorders.
{"title":"Genetic deletion of zinc transporter ZnT3 induces progressive cognitive deficits in mice by impairing dendritic spine plasticity and glucose metabolism","authors":"Rui Zong, Xiaoding Zhang, Xiaohui Dong, Guan Liu, Jieyao Zhang, Yiting Gao, Zhongyang Zhang, Yiming Ma, Haixia Gao, Nikita Gamper","doi":"10.3389/fnmol.2024.1375925","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1375925","url":null,"abstract":"Zinc transporter 3 (ZnT<jats:sub>3</jats:sub>) is abundantly expressed in the brain, residing in synaptic vesicles, where it plays important roles in controlling the luminal zinc levels. In this study, we found that ZnT<jats:sub>3</jats:sub> knockout in mice decreased zinc levels in the hippocampus and cortex, and was associated with progressive cognitive impairments, assessed at 2, 6, and 9-month of age. The results of Golgi-Cox staining demonstrated that ZnT<jats:sub>3</jats:sub> deficiency was associated with an increase in dendritic complexity and a decrease in the density of mature dendritic spines, indicating potential synaptic plasticity deficit. Since ZnT<jats:sub>3</jats:sub> deficiency was previously linked to glucose metabolism abnormalities, we tested the expression levels of genes related to insulin signaling pathway in the hippocampus and cortex. We found that the Expression of glucose transporters, GLUT3, GLUT4, and the insulin receptor in the whole tissue and synaptosome fraction of the hippocampus of the ZnT<jats:sub>3</jats:sub> knockout mice were significantly reduced, as compared to wild-type controls. Expression of AKT (A serine/threonine protein kinase) and insulin-induced AKT phosphorylation was also reduced in the hippocampus of ZnT<jats:sub>3</jats:sub> knockout mice. We hypothesize that the ZnT<jats:sub>3</jats:sub> deficiency and reduced brain zinc levels may cause cognitive impairment by negatively affecting glycose metabolism via decreased expression of key components of insulin signaling, as well as via changes in synaptic plasticity. These finding may provide new therapeutic target for treatments of neurodegenerative disorders.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140932884","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}
Pub Date : 2024-05-14DOI: 10.3389/fnmol.2024.1386219
Erin E. Duffy, Elena G. Assad, Brian T. Kalish, Michael E. Greenberg
The mammalian central nervous system coordinates a network of signaling pathways and cellular interactions, which enable a myriad of complex cognitive and physiological functions. While traditional efforts to understand the molecular basis of brain function have focused on well-characterized proteins, recent advances in high-throughput translatome profiling have revealed a staggering number of proteins translated from non-canonical open reading frames (ncORFs) such as 5′ and 3′ untranslated regions of annotated proteins, out-of-frame internal ORFs, and previously annotated non-coding RNAs. Of note, microproteins < 100 amino acids (AA) that are translated from such ncORFs have often been neglected due to computational and biochemical challenges. Thousands of putative microproteins have been identified in cell lines and tissues including the brain, with some serving critical biological functions. In this perspective, we highlight the recent discovery of microproteins in the brain and describe several hypotheses that have emerged concerning microprotein function in the developing and mature nervous system.
{"title":"Small but mighty: the rise of microprotein biology in neuroscience","authors":"Erin E. Duffy, Elena G. Assad, Brian T. Kalish, Michael E. Greenberg","doi":"10.3389/fnmol.2024.1386219","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1386219","url":null,"abstract":"The mammalian central nervous system coordinates a network of signaling pathways and cellular interactions, which enable a myriad of complex cognitive and physiological functions. While traditional efforts to understand the molecular basis of brain function have focused on well-characterized proteins, recent advances in high-throughput translatome profiling have revealed a staggering number of proteins translated from non-canonical open reading frames (ncORFs) such as 5′ and 3′ untranslated regions of annotated proteins, out-of-frame internal ORFs, and previously annotated non-coding RNAs. Of note, microproteins &lt; 100 amino acids (AA) that are translated from such ncORFs have often been neglected due to computational and biochemical challenges. Thousands of putative microproteins have been identified in cell lines and tissues including the brain, with some serving critical biological functions. In this perspective, we highlight the recent discovery of microproteins in the brain and describe several hypotheses that have emerged concerning microprotein function in the developing and mature nervous system.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140932860","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}
Pub Date : 2024-05-13DOI: 10.3389/fnmol.2024.1371086
Kevin Jonischkies, Miguel del Angel, Yunus Emre Demiray, Allison Loaiza Zambrano, Oliver Stork
Aging is defined as a progressive decline of cognitive and physiological functions over lifetime. Since the definition of the nine hallmarks of aging in 2013 by López-Otin, numerous studies have attempted to identify the main regulators and contributors in the aging process. One interesting group of proteins whose participation has been implicated in several aging hallmarks are the nuclear DBF2-related (NDR) family of serine-threonine AGC kinases. They are one of the core components of the Hippo signaling pathway and include NDR1, NDR2, LATS1 and LATS2 in mammals, along with its highly conserved metazoan orthologs; Trc in Drosophila melanogaster, SAX-1 in Caenorhabditis elegans, CBK1, DBF20 in Saccharomyces cerevisiae and orb6 in Saccharomyces pombe. These kinases have been independently linked to the regulation of widely diverse cellular processes disrupted during aging such as the cell cycle progression, transcription, intercellular communication, nutrient homeostasis, autophagy, apoptosis, and stem cell differentiation. However, a comprehensive overview of the state-of-the-art knowledge regarding the post-translational modifications of and by NDR kinases in aging has not been conducted. In this review, we summarize the current understanding of the NDR family of kinases, focusing on their relevance to various aging hallmarks, and emphasize the growing body of evidence that suggests NDR kinases are essential regulators of aging across species.
{"title":"The NDR family of kinases: essential regulators of aging","authors":"Kevin Jonischkies, Miguel del Angel, Yunus Emre Demiray, Allison Loaiza Zambrano, Oliver Stork","doi":"10.3389/fnmol.2024.1371086","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1371086","url":null,"abstract":"Aging is defined as a progressive decline of cognitive and physiological functions over lifetime. Since the definition of the nine hallmarks of aging in 2013 by López-Otin, numerous studies have attempted to identify the main regulators and contributors in the aging process. One interesting group of proteins whose participation has been implicated in several aging hallmarks are the nuclear DBF2-related (NDR) family of serine-threonine AGC kinases. They are one of the core components of the Hippo signaling pathway and include NDR1, NDR2, LATS1 and LATS2 in mammals, along with its highly conserved metazoan orthologs; Trc in <jats:italic>Drosophila melanogaster</jats:italic>, SAX-1 in <jats:italic>Caenorhabditis elegans</jats:italic>, CBK1, DBF20 in <jats:italic>Saccharomyces cerevisiae</jats:italic> and orb6 in <jats:italic>Saccharomyces pombe</jats:italic>. These kinases have been independently linked to the regulation of widely diverse cellular processes disrupted during aging such as the cell cycle progression, transcription, intercellular communication, nutrient homeostasis, autophagy, apoptosis, and stem cell differentiation. However, a comprehensive overview of the state-of-the-art knowledge regarding the post-translational modifications of and by NDR kinases in aging has not been conducted. In this review, we summarize the current understanding of the NDR family of kinases, focusing on their relevance to various aging hallmarks, and emphasize the growing body of evidence that suggests NDR kinases are essential regulators of aging across species.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140933088","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}
Pub Date : 2024-05-10DOI: 10.3389/fnmol.2024.1376997
David Micinski, Pirta Hotulainen
The location of the axon initial segment (AIS) at the junction between the soma and axon of neurons makes it instrumental in maintaining neural polarity and as the site for action potential generation. The AIS is also capable of large-scale relocation in an activity-dependent manner. This represents a form of homeostatic plasticity in which neurons regulate their own excitability by changing the size and/or position of the AIS. While AIS plasticity is important for proper functionality of AIS-containing neurons, the cellular and molecular mechanisms of AIS plasticity are poorly understood. Here, we analyzed changes in the AIS actin cytoskeleton during AIS plasticity using 3D structured illumination microscopy (3D-SIM). We showed that the number of longitudinal actin fibers increased transiently 3 h after plasticity induction. We further showed that actin polymerization, especially formin mediated actin polymerization, is required for AIS plasticity and formation of longitudinal actin fibers. From the formin family of proteins, Daam1 localized to the ends of longitudinal actin fibers. These results indicate that active re-organization of the actin cytoskeleton is required for proper AIS plasticity.
{"title":"Actin polymerization and longitudinal actin fibers in axon initial segment plasticity","authors":"David Micinski, Pirta Hotulainen","doi":"10.3389/fnmol.2024.1376997","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1376997","url":null,"abstract":"The location of the axon initial segment (AIS) at the junction between the soma and axon of neurons makes it instrumental in maintaining neural polarity and as the site for action potential generation. The AIS is also capable of large-scale relocation in an activity-dependent manner. This represents a form of homeostatic plasticity in which neurons regulate their own excitability by changing the size and/or position of the AIS. While AIS plasticity is important for proper functionality of AIS-containing neurons, the cellular and molecular mechanisms of AIS plasticity are poorly understood. Here, we analyzed changes in the AIS actin cytoskeleton during AIS plasticity using 3D structured illumination microscopy (3D-SIM). We showed that the number of longitudinal actin fibers increased transiently 3 h after plasticity induction. We further showed that actin polymerization, especially formin mediated actin polymerization, is required for AIS plasticity and formation of longitudinal actin fibers. From the formin family of proteins, Daam1 localized to the ends of longitudinal actin fibers. These results indicate that active re-organization of the actin cytoskeleton is required for proper AIS plasticity.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140932877","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}
Pub Date : 2024-05-09DOI: 10.3389/fnmol.2024.1398839
Munal B. Kandel, Gerald Z. Zhuang, William F. Goins, Marco Marzulli, Mingdi Zhang, Joseph C. Glorioso, Yuan Kang, Alexandra E. Levitt, Wai-Meng Kwok, Roy C. Levitt, Konstantinos D. Sarantopoulos
Chronic pain is common and inadequately treated, making the development of safe and effective analgesics a high priority. Our previous data indicate that carbonic anhydrase-8 (CA8) expression in dorsal root ganglia (DRG) mediates analgesia via inhibition of neuronal ER inositol trisphosphate receptor-1 (ITPR1) via subsequent decrease in ER calcium release and reduction of cytoplasmic free calcium, essential to the regulation of neuronal excitability. This study tested the hypothesis that novel JDNI8 replication-defective herpes simplex-1 viral vectors (rdHSV) carrying a CA8 transgene (vHCA8) reduce primary afferent neuronal excitability. Whole-cell current clamp recordings in small DRG neurons showed that vHCA8 transduction caused prolongation of their afterhyperpolarization (AHP), an essential regulator of neuronal excitability. This AHP prolongation was completely reversed by the specific Kv7 channel inhibitor XE-991. Voltage clamp recordings indicate an effect via Kv7 channels in vHCA8-infected small DRG neurons. These data demonstrate for the first time that vHCA8 produces Kv7 channel activation, which decreases neuronal excitability in nociceptors. This suppression of excitability may translate in vivo as non-opioid dependent behavioral- or clinical analgesia, if proven behaviorally and clinically.
{"title":"rdHSV-CA8 non-opioid analgesic gene therapy decreases somatosensory neuronal excitability by activating Kv7 voltage-gated potassium channels","authors":"Munal B. Kandel, Gerald Z. Zhuang, William F. Goins, Marco Marzulli, Mingdi Zhang, Joseph C. Glorioso, Yuan Kang, Alexandra E. Levitt, Wai-Meng Kwok, Roy C. Levitt, Konstantinos D. Sarantopoulos","doi":"10.3389/fnmol.2024.1398839","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1398839","url":null,"abstract":"Chronic pain is common and inadequately treated, making the development of safe and effective analgesics a high priority. Our previous data indicate that carbonic anhydrase-8 (CA8) expression in dorsal root ganglia (DRG) mediates analgesia via inhibition of neuronal ER inositol trisphosphate receptor-1 (ITPR1) via subsequent decrease in ER calcium release and reduction of cytoplasmic free calcium, essential to the regulation of neuronal excitability. This study tested the hypothesis that novel JDNI8 replication-defective herpes simplex-1 viral vectors (rdHSV) carrying a CA8 transgene (vHCA8) reduce primary afferent neuronal excitability. Whole-cell current clamp recordings in small DRG neurons showed that vHCA8 transduction caused prolongation of their afterhyperpolarization (AHP), an essential regulator of neuronal excitability. This AHP prolongation was completely reversed by the specific Kv7 channel inhibitor XE-991. Voltage clamp recordings indicate an effect via Kv7 channels in vHCA8-infected small DRG neurons. These data demonstrate for the first time that vHCA8 produces Kv7 channel activation, which decreases neuronal excitability in nociceptors. This suppression of excitability may translate <jats:italic>in vivo</jats:italic> as non-opioid dependent behavioral- or clinical analgesia, if proven behaviorally and clinically.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140932862","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}
Pub Date : 2024-05-09DOI: 10.3389/fnmol.2024.1381534
Kaylie Robinson, Mathias Delhaye, Ann Marie Craig
Functions of the cerebellar cortex, from motor learning to emotion and cognition, depend on the appropriate molecular composition at diverse synapse types. Glutamate receptor distributions have been partially mapped using immunogold electron microscopy. However, information is lacking on the distribution of many other components, such as Shank2, a postsynaptic scaffolding protein whose cerebellar dysfunction is associated with autism spectrum disorders. Here, we used an adapted Magnified Analysis of the Proteome, an expansion microscopy approach, to map multiple glutamate receptors, scaffolding and signaling proteins at single synapse resolution in the cerebellar cortex. Multiple distinct synapse-selective distribution patterns were observed. For example, AMPA receptors were most concentrated at synapses on molecular layer interneurons and at climbing fiber synapses, Shank1 was most concentrated at parallel fiber synapses on Purkinje cells, and Shank2 at both climbing fiber and parallel fiber synapses on Purkinje cells but little on molecular layer interneurons. Our results are consistent with gene expression data but also reveal input-selective targeting within Purkinje cells. In specialized glomerular structures of the granule cell layer, AMPA receptors as well as most other synaptic components preferentially targeted to synapses. However, NMDA receptors and the synaptic GTPase activating protein SynGAP preferentially targeted to extrasynaptic sites. Thus, glomeruli may be considered integrative signaling units through which mossy fibers differentially activate synaptic AMPA and extrasynaptic NMDA receptor complexes. Furthermore, we observed NMDA receptors and SynGAP at adherens junctions, suggesting a role in structural plasticity of glomeruli. Altogether, these data contribute to mapping the cerebellar ‘synaptome’.
{"title":"Mapping proteomic composition of excitatory postsynaptic sites in the cerebellar cortex","authors":"Kaylie Robinson, Mathias Delhaye, Ann Marie Craig","doi":"10.3389/fnmol.2024.1381534","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1381534","url":null,"abstract":"Functions of the cerebellar cortex, from motor learning to emotion and cognition, depend on the appropriate molecular composition at diverse synapse types. Glutamate receptor distributions have been partially mapped using immunogold electron microscopy. However, information is lacking on the distribution of many other components, such as Shank2, a postsynaptic scaffolding protein whose cerebellar dysfunction is associated with autism spectrum disorders. Here, we used an adapted Magnified Analysis of the Proteome, an expansion microscopy approach, to map multiple glutamate receptors, scaffolding and signaling proteins at single synapse resolution in the cerebellar cortex. Multiple distinct synapse-selective distribution patterns were observed. For example, AMPA receptors were most concentrated at synapses on molecular layer interneurons and at climbing fiber synapses, Shank1 was most concentrated at parallel fiber synapses on Purkinje cells, and Shank2 at both climbing fiber and parallel fiber synapses on Purkinje cells but little on molecular layer interneurons. Our results are consistent with gene expression data but also reveal input-selective targeting within Purkinje cells. In specialized glomerular structures of the granule cell layer, AMPA receptors as well as most other synaptic components preferentially targeted to synapses. However, NMDA receptors and the synaptic GTPase activating protein SynGAP preferentially targeted to extrasynaptic sites. Thus, glomeruli may be considered integrative signaling units through which mossy fibers differentially activate synaptic AMPA and extrasynaptic NMDA receptor complexes. Furthermore, we observed NMDA receptors and SynGAP at adherens junctions, suggesting a role in structural plasticity of glomeruli. Altogether, these data contribute to mapping the cerebellar ‘synaptome’.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140932885","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}
Pub Date : 2024-05-09DOI: 10.3389/fnmol.2024.1160435
Haiyan Zheng, Minseok Kim, Chaeun Kim, Yerin Kim, Pyung Sun Cho, Ji Yeon Lim, Hojin Lee, Hye-In Yun, Jungmin Choi, Sun Wook Hwang
The function of peripheral nociceptors, the neurons that relay pain signals to the brain, are frequently tuned by local and systemic modulator substances. In this context, neurohormonal effects are emerging as an important modulatory mechanism, but many aspects remain to be elucidated. Here we report that gonadotropin-releasing hormone (GnRH), a brain-specific neurohormone, can aggravate pain by acting on nociceptors in mice. GnRH and GnRHR, the receptor for GnRH, are expressed in a nociceptor subpopulation. Administration of GnRH and its analogue, localized for selectively affecting the peripheral neurons, deteriorated mechanical pain, which was reproducible in neuropathic conditions. Nociceptor function was promoted by GnRH treatment in vitro, which appears to involve specific sensory transient receptor potential ion channels. These data suggest that peripheral GnRH can positively modulate nociceptor activities in its receptor-specific manner, contributing to pain exacerbation. Our study indicates that GnRH plays an important role in neurohormonal pain modulation via a peripheral mechanism.
{"title":"GnRH peripherally modulates nociceptor functions, exacerbating mechanical pain","authors":"Haiyan Zheng, Minseok Kim, Chaeun Kim, Yerin Kim, Pyung Sun Cho, Ji Yeon Lim, Hojin Lee, Hye-In Yun, Jungmin Choi, Sun Wook Hwang","doi":"10.3389/fnmol.2024.1160435","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1160435","url":null,"abstract":"The function of peripheral nociceptors, the neurons that relay pain signals to the brain, are frequently tuned by local and systemic modulator substances. In this context, neurohormonal effects are emerging as an important modulatory mechanism, but many aspects remain to be elucidated. Here we report that gonadotropin-releasing hormone (GnRH), a brain-specific neurohormone, can aggravate pain by acting on nociceptors in mice. GnRH and GnRHR, the receptor for GnRH, are expressed in a nociceptor subpopulation. Administration of GnRH and its analogue, localized for selectively affecting the peripheral neurons, deteriorated mechanical pain, which was reproducible in neuropathic conditions. Nociceptor function was promoted by GnRH treatment <jats:italic>in vitro</jats:italic>, which appears to involve specific sensory transient receptor potential ion channels. These data suggest that peripheral GnRH can positively modulate nociceptor activities in its receptor-specific manner, contributing to pain exacerbation. Our study indicates that GnRH plays an important role in neurohormonal pain modulation via a peripheral mechanism.","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140932850","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}
Pub Date : 2024-05-02DOI: 10.3389/fnmol.2024.1379743
Marie-Pierre Pasdelou, Lise Byelyayeva, Susanna Malmström, Sylvie Pucheu, Marie Peytavy, Hugo Laullier, Donald B. Hodges, Abraham R. Tzafriri, Gaëlle Naert
Hearing loss constitutes a major global health concern impacting approximately 1.5 billion people worldwide. Its incidence is undergoing a substantial surge with some projecting that by 2050, a quarter of the global population will experience varying degrees of hearing deficiency. Environmental factors such as aging, exposure to loud noise, and the intake of ototoxic medications are implicated in the onset of acquired hearing loss. Ototoxicity resulting in inner ear damage is a leading cause of acquired hearing loss worldwide. This could be minimized or avoided by early testing of hearing functions in the preclinical phase of drug development. While the assessment of ototoxicity is well defined for drug candidates in the hearing field – required for drugs that are administered by the otic route and expected to reach the middle or inner ear during clinical use – ototoxicity testing is not required for all other therapeutic areas. Unfortunately, this has resulted in more than 200 ototoxic marketed medications. The aim of this publication is to raise awareness of drug-induced ototoxicity and to formulate some recommendations based on available guidelines and own experience. Ototoxicity testing programs should be adapted to the type of therapy, its indication (targeting the ear or part of other medications classes being potentially ototoxic), and the number of assets to test. For multiple molecules and/or multiple doses, screening options are available: in vitro (otic cell assays), ex vivo (cochlear explant), and in vivo (in zebrafish). In assessing the ototoxicity of a candidate drug, it is good practice to compare its ototoxicity to that of a well-known control drug of a similar class. Screening assays provide a streamlined and rapid method to know whether a drug is generally safe for inner ear structures. Mammalian animal models provide a more detailed characterization of drug ototoxicity, with a possibility to localize and quantify the damage using functional, behavioral, and morphological read-outs. Complementary histological measures are routinely conducted notably to quantify hair cells loss with cochleogram. Ototoxicity studies can be performed in rodents (mice, rats), guinea pigs and large species. However, in undertaking, or at the very least attempting, all preclinical investigations within the same species, is crucial. This encompasses starting with pharmacokinetics and pharmacology efficacy studies and extending through to toxicity studies. In life read-outs include Auditory Brainstem Response (ABR) and Distortion Product OtoAcoustic Emissions (DPOAE) measurements that assess the activity and integrity of sensory cells and the auditory nerve, reflecting sensorineural hearing loss. Accurate, reproducible, and high throughput ABR measures are fundamental to the quality and success of these preclinical trials. As in humans, in vivo ot
听力损失是一个重大的全球健康问题，影响着全球约 15 亿人。听力损失的发病率正急剧上升，有人预计到 2050 年，全球四分之一的人口将出现不同程度的听力障碍。后天性听力损失的发病与环境因素有关，如衰老、暴露于高噪音环境和摄入耳毒性药物。耳毒性导致内耳损伤是全球后天性听力损失的主要原因。如果在药物开发的临床前阶段及早检测听力功能，就可以最大限度地减少或避免这种情况的发生。虽然听力领域候选药物的耳毒性评估已经有了明确的规定--通过耳道给药并有望在临床使用中到达中耳或内耳的药物必须进行耳毒性测试，但所有其他治疗领域的药物都不需要进行耳毒性测试。遗憾的是，这导致市场上出现了 200 多种耳毒性药物。本出版物旨在提高人们对药物诱发耳毒性的认识，并根据现有指南和自身经验提出一些建议。耳毒性检测计划应根据治疗类型、适应症（针对耳部或其他可能具有耳毒性的药物类别的一部分）以及需要检测的资产数量进行调整。对于多种分子和/或多种剂量的药物，可选择体外（耳细胞试验）、体外（耳蜗移植）和体内（斑马鱼）筛选。在评估候选药物的耳毒性时，好的做法是将其耳毒性与知名的同类对照药物的耳毒性进行比较。筛选试验提供了一种简化而快速的方法，可用于了解药物对内耳结构是否普遍安全。哺乳动物模型能更详细地描述药物的耳毒性，并能利用功能、行为和形态读数对损伤进行定位和量化。此外，还可通过耳蜗图量化毛细胞的损失。耳毒性研究可在啮齿动物（小鼠、大鼠）、豚鼠和大型动物中进行。然而，在同一物种内进行或至少尝试进行所有临床前研究是至关重要的。这包括从药代动力学和药理学疗效研究开始，一直延伸到毒性研究。生活中的读数包括听性脑干反应（ABR）和失真产物声发射（DPOAE）测量，用于评估感觉细胞和听觉神经的活性和完整性，反映感音神经性听力损失。准确、可重复和高通量的 ABR 测量是这些临床前试验的质量和成功的基础。与人类一样，体内耳镜评估也是观察鼓膜和听道的常规方法。这通常是为了检测炎症迹象。耳蜗是一个音调结构。毛细胞的反应性与位置和频率有关，靠近耳蜗顶端的毛细胞可传递低频，而位于底部的毛细胞则可传递高频。耳蜗图旨在量化整个耳蜗的毛细胞，从而确定与特定频率相关的毛细胞损失。然后将这一测量结果与 ABR & DPOAE 结果相关联。耳毒性评估可评估候选药物对听觉和前庭系统的影响，降低听力损失和平衡失调的风险，确定安全剂量，优化治疗效果。这类研究可在治疗方案的早期开发阶段通过 ABR 和耳镜评估启动。根据化合物的作用机制，研究可包括 DPOAE 和耳蜗图。在研发后期，根据与耳部相关的给药途径、目标或已知的潜在耳毒性，可能需要进行 GLP（良好实验室规范）耳毒性研究。
{"title":"Ototoxicity: a high risk to auditory function that needs to be monitored in drug development","authors":"Marie-Pierre Pasdelou, Lise Byelyayeva, Susanna Malmström, Sylvie Pucheu, Marie Peytavy, Hugo Laullier, Donald B. Hodges, Abraham R. Tzafriri, Gaëlle Naert","doi":"10.3389/fnmol.2024.1379743","DOIUrl":"https://doi.org/10.3389/fnmol.2024.1379743","url":null,"abstract":"Hearing loss constitutes a major global health concern impacting approximately 1.5 billion people worldwide. Its incidence is undergoing a substantial surge with some projecting that by 2050, a quarter of the global population will experience varying degrees of hearing deficiency. Environmental factors such as aging, exposure to loud noise, and the intake of ototoxic medications are implicated in the onset of acquired hearing loss. Ototoxicity resulting in inner ear damage is a leading cause of acquired hearing loss worldwide. This could be minimized or avoided by early testing of hearing functions in the preclinical phase of drug development. While the assessment of ototoxicity is well defined for drug candidates in the hearing field – required for drugs that are administered by the otic route and expected to reach the middle or inner ear during clinical use – ototoxicity testing is not required for all other therapeutic areas. Unfortunately, this has resulted in more than 200 ototoxic marketed medications. The aim of this publication is to raise awareness of drug-induced ototoxicity and to formulate some recommendations based on available guidelines and own experience. Ototoxicity testing programs should be adapted to the type of therapy, its indication (targeting the ear or part of other medications classes being potentially ototoxic), and the number of assets to test. For multiple molecules and/or multiple doses, screening options are available: <jats:italic>in vitro</jats:italic> (otic cell assays), <jats:italic>ex vivo</jats:italic> (cochlear explant), and <jats:italic>in vivo</jats:italic> (in zebrafish). In assessing the ototoxicity of a candidate drug, it is good practice to compare its ototoxicity to that of a well-known control drug of a similar class. Screening assays provide a streamlined and rapid method to know whether a drug is generally safe for inner ear structures. Mammalian animal models provide a more detailed characterization of drug ototoxicity, with a possibility to localize and quantify the damage using functional, behavioral, and morphological read-outs. Complementary histological measures are routinely conducted notably to quantify hair cells loss with cochleogram. Ototoxicity studies can be performed in rodents (mice, rats), guinea pigs and large species. However, in undertaking, or at the very least attempting, all preclinical investigations within the same species, is crucial. This encompasses starting with pharmacokinetics and pharmacology efficacy studies and extending through to toxicity studies. In life read-outs include Auditory Brainstem Response (ABR) and Distortion Product OtoAcoustic Emissions (DPOAE) measurements that assess the activity and integrity of sensory cells and the auditory nerve, reflecting sensorineural hearing loss. Accurate, reproducible, and high throughput ABR measures are fundamental to the quality and success of these preclinical trials. As in humans, <jats:italic>in vivo</jats:italic> ot","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140829349","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}
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