Pub Date : 2024-10-16eCollection Date: 2024-01-01DOI: 10.3389/fncel.2024.1474231
Lin Lin, Xiaofei Hu, Weijun Hong, Tengwei Pan, Zhiren Wang, En Wang, Gang Wu
Changes in neurovascular unit components and their interactions play a crucial role in epileptogenesis and the pathological process of epilepsy. Currently, there is a lack of animal models that can accurately reflect the etiological impact of cerebrovascular lesions on epilepsy. In this study, we constructed cyclin-dependent kinase 5 conditional knockout mice in Cspg4 (pericyte marker)-positive cells using the Cre-LoxP system. The results revealed that this strain of mice exhibited significant seizure behaviors and epileptiform brain waves, loss of hippocampal and amygdala neurons, astrogliosis, decreased pericyte coverage, and reduced AQP4 polar distribution. Herein, we have developed a novel mouse model of spontaneous epilepsy, providing a critical animal model for studying the involvement of neurovascular unit factors in the development and progression of epilepsy.
{"title":"A novel animal model of spontaneous epilepsy: Cdk5 knockout in pericyte-specific mice.","authors":"Lin Lin, Xiaofei Hu, Weijun Hong, Tengwei Pan, Zhiren Wang, En Wang, Gang Wu","doi":"10.3389/fncel.2024.1474231","DOIUrl":"10.3389/fncel.2024.1474231","url":null,"abstract":"<p><p>Changes in neurovascular unit components and their interactions play a crucial role in epileptogenesis and the pathological process of epilepsy. Currently, there is a lack of animal models that can accurately reflect the etiological impact of cerebrovascular lesions on epilepsy. In this study, we constructed cyclin-dependent kinase 5 conditional knockout mice in Cspg4 (pericyte marker)-positive cells using the Cre-LoxP system. The results revealed that this strain of mice exhibited significant seizure behaviors and epileptiform brain waves, loss of hippocampal and amygdala neurons, astrogliosis, decreased pericyte coverage, and reduced AQP4 polar distribution. Herein, we have developed a novel mouse model of spontaneous epilepsy, providing a critical animal model for studying the involvement of neurovascular unit factors in the development and progression of epilepsy.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11521856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544689","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}
Pub Date : 2024-10-16eCollection Date: 2024-01-01DOI: 10.3389/fncel.2024.1466056
Estelle Renaux, Charlotte Baudouin, Olivier Schakman, Ondine Gay, Manon Martin, Damien Marchese, Younès Achouri, René Rezsohazy, Françoise Gofflot, Frédéric Clotman
Motor activity is organized by neuronal networks composed of motor neurons and a wide variety of pre-motor interneuron populations located in the brainstem and spinal cord. Differential expression and single-cell RNA sequencing studies recently unveiled that these populations subdivide into multiple subsets. However, some interneuron subsets have not been described yet, and the mechanisms contributing to this neuronal diversification have only been partly deciphered. In this study, we aimed to identify additional markers to further describe the diversity of spinal V2 interneuron populations. Here, we compared the transcriptome of V2 interneurons with that of the other cells of the embryonic spinal cord and extracted a list of genes enriched in V2 interneurons, including Arid3c. Arid3c identifies an uncharacterized subset of V2 that partially overlaps with V2c interneurons. These two populations are characterized by the production of Onecut factors and Sox2, suggesting that they could represent a single functional V2 unit. Furthermore, we show that the overexpression or inactivation of Arid3c does not alter V2 production, but its absence results in minor defects in locomotor execution, suggesting a possible function in subtle aspects of spinal locomotor circuit formation.
{"title":"Arid3c identifies an uncharacterized subpopulation of V2 interneurons during embryonic spinal cord development.","authors":"Estelle Renaux, Charlotte Baudouin, Olivier Schakman, Ondine Gay, Manon Martin, Damien Marchese, Younès Achouri, René Rezsohazy, Françoise Gofflot, Frédéric Clotman","doi":"10.3389/fncel.2024.1466056","DOIUrl":"10.3389/fncel.2024.1466056","url":null,"abstract":"<p><p>Motor activity is organized by neuronal networks composed of motor neurons and a wide variety of pre-motor interneuron populations located in the brainstem and spinal cord. Differential expression and single-cell RNA sequencing studies recently unveiled that these populations subdivide into multiple subsets. However, some interneuron subsets have not been described yet, and the mechanisms contributing to this neuronal diversification have only been partly deciphered. In this study, we aimed to identify additional markers to further describe the diversity of spinal V2 interneuron populations. Here, we compared the transcriptome of V2 interneurons with that of the other cells of the embryonic spinal cord and extracted a list of genes enriched in V2 interneurons, including <i>Arid3c</i>. Arid3c identifies an uncharacterized subset of V2 that partially overlaps with V2c interneurons. These two populations are characterized by the production of Onecut factors and Sox2, suggesting that they could represent a single functional V2 unit. Furthermore, we show that the overexpression or inactivation of <i>Arid3c</i> does not alter V2 production, but its absence results in minor defects in locomotor execution, suggesting a possible function in subtle aspects of spinal locomotor circuit formation.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11521906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544690","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}
Pub Date : 2024-10-16eCollection Date: 2024-01-01DOI: 10.3389/fncel.2024.1460262
Yunpeng Du, Shuhan Dong, Wei Zou
Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system CNS characterized by demyelination, inflammation, and neurodegenerative changes, making it the most common nontraumatic disabling neurological disease in young adults. While current pharmacological treatments primarily target immunomodulation or immunosuppression, exercise is gaining increasing attention from the scientific community as an adjunctive therapy. This review explores the potential biological mechanisms of exercise in animal models of MS, focusing on its effects on neuroprotection and inflammation. The review examines how exercise inhibits pro-inflammatory microglial reactivity, stabilizes the blood-brain barrier, and enhances neurotrophic factor expression in animal studies. Future research directions are proposed by summarizing the evidence and limitations of existing animal models of MS, emphasizing the need to further validate these mechanisms in humans to better integrate exercise into the comprehensive management of MS. Additionally, investigating exercise-induced biomarkers for MS symptom reduction may provide a scientific basis for new therapeutic strategies.
{"title":"Exploring the underlying mechanisms of exercise as therapy for multiple sclerosis: insights from preclinical studies.","authors":"Yunpeng Du, Shuhan Dong, Wei Zou","doi":"10.3389/fncel.2024.1460262","DOIUrl":"10.3389/fncel.2024.1460262","url":null,"abstract":"<p><p>Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system CNS characterized by demyelination, inflammation, and neurodegenerative changes, making it the most common nontraumatic disabling neurological disease in young adults. While current pharmacological treatments primarily target immunomodulation or immunosuppression, exercise is gaining increasing attention from the scientific community as an adjunctive therapy. This review explores the potential biological mechanisms of exercise in animal models of MS, focusing on its effects on neuroprotection and inflammation. The review examines how exercise inhibits pro-inflammatory microglial reactivity, stabilizes the blood-brain barrier, and enhances neurotrophic factor expression in animal studies. Future research directions are proposed by summarizing the evidence and limitations of existing animal models of MS, emphasizing the need to further validate these mechanisms in humans to better integrate exercise into the comprehensive management of MS. Additionally, investigating exercise-induced biomarkers for MS symptom reduction may provide a scientific basis for new therapeutic strategies.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11521911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544691","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}
Pub Date : 2024-10-15eCollection Date: 2024-01-01DOI: 10.3389/fncel.2024.1475934
Yifan Fei, Yifei Ding
Ferroptosis represents an iron- and lipid peroxidation (LPO)-mediated form of regulated cell death (RCD). Recent evidence strongly suggests the involvement of ferroptosis in various neurodegenerative diseases (NDs), particularly Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), among others. The treatment of ferroptosis poses both opportunities and challenges in the context of ND. This review provides a comprehensive overview of characteristic features, induction and inhibition of ferroptosis, highlighting the ferroptosis inhibitor and the underlying mechanisms responsible for its occurrence. Moreover, the review explores how these mechanisms contribute to the pathogenesis and progression of major neurodegenerative disorders. Additionally, it presents novel insights into the role of ferroptosis in ND and summarizes recent advancements in the development of therapeutic approaches targeting ferroptosis. These insights and advancements hold potential to guide future strategies aimed at effectively managing these debilitating medical conditions.
{"title":"The role of ferroptosis in neurodegenerative diseases.","authors":"Yifan Fei, Yifei Ding","doi":"10.3389/fncel.2024.1475934","DOIUrl":"https://doi.org/10.3389/fncel.2024.1475934","url":null,"abstract":"<p><p>Ferroptosis represents an iron<sup>-</sup> and lipid peroxidation (LPO)-mediated form of regulated cell death (RCD). Recent evidence strongly suggests the involvement of ferroptosis in various neurodegenerative diseases (NDs), particularly Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), among others. The treatment of ferroptosis poses both opportunities and challenges in the context of ND. This review provides a comprehensive overview of characteristic features, induction and inhibition of ferroptosis, highlighting the ferroptosis inhibitor and the underlying mechanisms responsible for its occurrence. Moreover, the review explores how these mechanisms contribute to the pathogenesis and progression of major neurodegenerative disorders. Additionally, it presents novel insights into the role of ferroptosis in ND and summarizes recent advancements in the development of therapeutic approaches targeting ferroptosis. These insights and advancements hold potential to guide future strategies aimed at effectively managing these debilitating medical conditions.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11518764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544693","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}
Pub Date : 2024-10-14eCollection Date: 2024-01-01DOI: 10.3389/fncel.2024.1465011
Paola Cavalli, Anna Raffauf, Sergio Passarella, Martin Helmuth, Daniela C Dieterich, Peter Landgraf
Deoxyhypusine synthase (DHPS) catalyzes the initial step of hypusine incorporation into the eukaryotic initiation factor 5A (eIF5A), leading to its activation. The activated eIF5A, in turn, plays a key role in regulating the protein translation of selected mRNAs and therefore appears to be a suitable target for therapeutic intervention strategies. In the present study, we analyzed the role of DHPS-mediated hypusination in regulating neuronal homeostasis using lentivirus-based gain and loss of function experiments in primary cortical cultures from rats. This model allows us to examine the impact of DHPS function on the composition of the dendritic and synaptic compartments, which may contribute to a better understanding of cognitive function and neurodevelopment in vivo. Our findings revealed that shRNA-mediated DHPS knockdown diminishes the amount of hypusinated eIF5A (eIF5AHyp), resulting in notable alterations in neuronal dendritic architecture. Furthermore, in neurons, the synaptic composition was also affected, showing both pre- and post-synaptic changes, while the overexpression of DHPS had only a minor impact. Therefore, we hypothesize that interfering with the eIF5A hypusination caused by reduced DHPS activity impairs neuronal and synaptic homeostasis.
{"title":"Manipulation of DHPS activity affects dendritic morphology and expression of synaptic proteins in primary rat cortical neurons.","authors":"Paola Cavalli, Anna Raffauf, Sergio Passarella, Martin Helmuth, Daniela C Dieterich, Peter Landgraf","doi":"10.3389/fncel.2024.1465011","DOIUrl":"10.3389/fncel.2024.1465011","url":null,"abstract":"<p><p>Deoxyhypusine synthase (DHPS) catalyzes the initial step of hypusine incorporation into the eukaryotic initiation factor 5A (eIF5A), leading to its activation. The activated eIF5A, in turn, plays a key role in regulating the protein translation of selected mRNAs and therefore appears to be a suitable target for therapeutic intervention strategies. In the present study, we analyzed the role of DHPS-mediated hypusination in regulating neuronal homeostasis using lentivirus-based gain and loss of function experiments in primary cortical cultures from rats. This model allows us to examine the impact of DHPS function on the composition of the dendritic and synaptic compartments, which may contribute to a better understanding of cognitive function and neurodevelopment <i>in vivo</i>. Our findings revealed that shRNA-mediated DHPS knockdown diminishes the amount of hypusinated eIF5A (eIF5A<sup>Hyp</sup>), resulting in notable alterations in neuronal dendritic architecture. Furthermore, in neurons, the synaptic composition was also affected, showing both pre- and post-synaptic changes, while the overexpression of DHPS had only a minor impact. Therefore, we hypothesize that interfering with the eIF5A hypusination caused by reduced DHPS activity impairs neuronal and synaptic homeostasis.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521536","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}
Pub Date : 2024-10-14eCollection Date: 2024-01-01DOI: 10.3389/fncel.2024.1477989
Rían W Manville, Claire L Illeck, Cesar Santos, Richard Sidlow, Geoffrey W Abbott
Human voltage-gated potassium (Kv) channels are expressed by a 40-member gene family that is essential for normal electrical activity and is closely linked to various excitability disorders. Function-altering sequence variants in the KCNB1 gene, which encodes the neuronally expressed Kv2.1 channel, are associated with neurodevelopmental disorders including developmental delay with or without epileptic activity. In this study, we describe a 40-month-old fraternal twin who presented with severe neurodevelopmental delay. Electroencephalogram recordings at 19 months of age revealed poor sleep architecture and the presence of multifocal epileptiform discharges. The individual's fraternal twin was neurotypical, and there was no family history of neurodevelopmental delay or seizures. Whole genome sequencing at 33 months of age for the proband revealed a de novo variant in KCNB1 [c.1154C > T/p.Pro385Leu], encoding a proline-to-leucine substitution at residue 385, in the extracellular region immediately preceding Kv2.1 transmembrane segment 6 (S6). Cellular electrophysiological analysis of the effects of the gene variant in heterologously expressed Kv2.1 demonstrated that homozygous Kv2.1-P385L channels were completely non-functional. Channels generated by a 50/50 expression of wild-type Kv2.1 and Kv2.1-P385L, designed to mimic the proband's heterozygous status, revealed a partially dominant-negative effect, resulting in an 81% reduction in current magnitude. The dramatic loss of function in Kv2.1 is the most likely cause of the severe developmental delay and seizure activity in the proband, further enriching our phenotypic understanding of KCNB1 developmental encephalopathies.
{"title":"A novel loss-of-function <i>KCNB1</i> gene variant in a twin with global developmental delay and seizures.","authors":"Rían W Manville, Claire L Illeck, Cesar Santos, Richard Sidlow, Geoffrey W Abbott","doi":"10.3389/fncel.2024.1477989","DOIUrl":"10.3389/fncel.2024.1477989","url":null,"abstract":"<p><p>Human voltage-gated potassium (Kv) channels are expressed by a 40-member gene family that is essential for normal electrical activity and is closely linked to various excitability disorders. Function-altering sequence variants in the <i>KCNB1</i> gene, which encodes the neuronally expressed Kv2.1 channel, are associated with neurodevelopmental disorders including developmental delay with or without epileptic activity. In this study, we describe a 40-month-old fraternal twin who presented with severe neurodevelopmental delay. Electroencephalogram recordings at 19 months of age revealed poor sleep architecture and the presence of multifocal epileptiform discharges. The individual's fraternal twin was neurotypical, and there was no family history of neurodevelopmental delay or seizures. Whole genome sequencing at 33 months of age for the proband revealed a <i>de novo</i> variant in <i>KCNB1</i> [c.1154C > T/p.Pro385Leu], encoding a proline-to-leucine substitution at residue 385, in the extracellular region immediately preceding Kv2.1 transmembrane segment 6 (S6). Cellular electrophysiological analysis of the effects of the gene variant in heterologously expressed Kv2.1 demonstrated that homozygous Kv2.1-P385L channels were completely non-functional. Channels generated by a 50/50 expression of wild-type Kv2.1 and Kv2.1-P385L, designed to mimic the proband's heterozygous status, revealed a partially dominant-negative effect, resulting in an 81% reduction in current magnitude. The dramatic loss of function in Kv2.1 is the most likely cause of the severe developmental delay and seizure activity in the proband, further enriching our phenotypic understanding of <i>KCNB1</i> developmental encephalopathies.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513283/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521535","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}
Pub Date : 2024-10-11eCollection Date: 2024-01-01DOI: 10.3389/fncel.2024.1465531
Marc André Ackermann, Susanne Monika Buchholz, Katharina Dietrich, Michael Müller
Spreading depolarization (SD) causes a massive neuronal/glial depolarization, disturbs ionic homeostasis and deranges neuronal network function. The metabolic burden imposed by SD may also generate marked amounts of reactive oxygen species (ROS). Yet, proper optical tools are required to study this aspect with spatiotemporal detail. Therefore, we earlier generated transgenic redox indicator mice. They express in excitatory projection neurons the cytosolic redox-sensor roGFP, a reduction/oxidation sensitive green fluorescent protein which is ratiometric by excitation and responds reversibly to redox alterations. Using adult male roGFPc mice, we analyzed SD-related ROS production in CA1 stratum pyramidale of submerged slices. SD was induced by K+ microinjection, O2 withdrawal or mitochondrial uncoupling (FCCP). The extracellular DC potential deflection was accompanied by a spreading wavefront of roGFP oxidation, confirming marked neuronal ROS generation. Hypoxia-induced SD was preceded by a moderate oxidation, which became intensified as the DC potential deflection occurred. Upon K+-induced SD, roGFP oxidation slowly recovered within 10-15 min in some slices. Upon FCCP-or hypoxia-induced SD, recovery was limited. Withdrawing extracellular Ca2+ markedly dampened the SD-related roGFP oxidation and improved its reversibility, confirming a key-role of neuronal Ca2+ load in SD-related ROS generation. Neither mitochondrial uncoupling, nor inhibition of NADPH oxidase or xanthine oxidase abolished the SD-related roGFP oxidation. Therefore, ROS generation during SD involves mitochondria as well as non-mitochondrial sources. This first-time analysis of SD-related ROS dynamics became possible based on quantitative redox imaging in roGFP mice, an advanced approach, which will contribute to further decipher the molecular understanding of SD in brain pathophysiology.
{"title":"Quantitative, real-time imaging of spreading depolarization-associated neuronal ROS production.","authors":"Marc André Ackermann, Susanne Monika Buchholz, Katharina Dietrich, Michael Müller","doi":"10.3389/fncel.2024.1465531","DOIUrl":"https://doi.org/10.3389/fncel.2024.1465531","url":null,"abstract":"<p><p>Spreading depolarization (SD) causes a massive neuronal/glial depolarization, disturbs ionic homeostasis and deranges neuronal network function. The metabolic burden imposed by SD may also generate marked amounts of reactive oxygen species (ROS). Yet, proper optical tools are required to study this aspect with spatiotemporal detail. Therefore, we earlier generated transgenic redox indicator mice. They express in excitatory projection neurons the cytosolic redox-sensor roGFP, a reduction/oxidation sensitive green fluorescent protein which is ratiometric by excitation and responds reversibly to redox alterations. Using adult male roGFPc mice, we analyzed SD-related ROS production in CA1 <i>stratum pyramidale</i> of submerged slices. SD was induced by K<sup>+</sup> microinjection, O<sub>2</sub> withdrawal or mitochondrial uncoupling (FCCP). The extracellular DC potential deflection was accompanied by a spreading wavefront of roGFP oxidation, confirming marked neuronal ROS generation. Hypoxia-induced SD was preceded by a moderate oxidation, which became intensified as the DC potential deflection occurred. Upon K<sup>+</sup>-induced SD, roGFP oxidation slowly recovered within 10-15 min in some slices. Upon FCCP-or hypoxia-induced SD, recovery was limited. Withdrawing extracellular Ca<sup>2+</sup> markedly dampened the SD-related roGFP oxidation and improved its reversibility, confirming a key-role of neuronal Ca<sup>2+</sup> load in SD-related ROS generation. Neither mitochondrial uncoupling, nor inhibition of NADPH oxidase or xanthine oxidase abolished the SD-related roGFP oxidation. Therefore, ROS generation during SD involves mitochondria as well as non-mitochondrial sources. This first-time analysis of SD-related ROS dynamics became possible based on quantitative redox imaging in roGFP mice, an advanced approach, which will contribute to further decipher the molecular understanding of SD in brain pathophysiology.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11519816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142544692","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}
Pub Date : 2024-10-10eCollection Date: 2024-01-01DOI: 10.3389/fncel.2024.1472374
Tereza Filipi, Jana Tureckova, Ondrej Vanatko, Martina Chmelova, Monika Kubiskova, Natalia Sirotova, Stanislava Matejkova, Lydia Vargova, Miroslava Anderova
Astrocytes are crucial for the functioning of the nervous system as they maintain the ion homeostasis via volume regulation. Pathological states, such as amyotrophic lateral sclerosis (ALS), affect astrocytes and might even cause a loss of such functions. In this study, we examined astrocytic swelling/volume recovery in both the brain and spinal cord of the SOD1 animal model to determine the level of their impairment caused by the ALS-like pathology. Astrocyte volume changes were measured in acute brain or spinal cord slices during and after exposure to hyperkalemia. We then compared the results with alterations of extracellular space (ECS) diffusion parameters, morphological changes, expression of the Kir4.1 channel and the potassium concentration measured in the cerebrospinal fluid, to further disclose the link between potassium and astrocytes in the ALS-like pathology. Morphological analysis revealed astrogliosis in both the motor cortex and the ventral horns of the SOD1 spinal cord. The activated morphology of SOD1 spinal astrocytes was associated with the results from volume measurements, which showed decreased swelling of these cells during hyperkalemia. Furthermore, we observed lower shrinkage of ECS in the SOD1 spinal ventral horns. Immunohistochemical analysis then confirmed decreased expression of the Kir4.1 channel in the SOD1 spinal cord, which corresponded with the diminished volume regulation. Despite astrogliosis, cortical astrocytes in SOD1 mice did not show alterations in swelling nor changes in Kir4.1 expression, and we did not identify significant changes in ECS parameters. Moreover, the potassium level in the cerebrospinal fluid did not deviate from the physiological concentration. The results we obtained thus suggest that ALS-like pathology causes impaired potassium uptake associated with Kir4.1 downregulation in the spinal astrocytes, but based on our data from the cortex, the functional impairment seems to be independent of the morphological state.
星形胶质细胞对神经系统的运作至关重要,因为它们通过体积调节维持离子平衡。病理状态(如肌萎缩性脊髓侧索硬化症(ALS))会影响星形胶质细胞,甚至可能导致其丧失上述功能。在这项研究中,我们检测了 SOD1 动物模型大脑和脊髓中星形胶质细胞的肿胀/体积恢复情况,以确定 ALS 类病变对它们的损害程度。我们测量了急性脑或脊髓切片在暴露于高钾血症期间和之后的星形胶质细胞体积变化。然后,我们将结果与细胞外空间(ECS)扩散参数的变化、形态学变化、Kir4.1通道的表达以及脑脊液中测得的钾浓度进行了比较,以进一步揭示钾与星形胶质细胞在ALS样病理中的联系。形态学分析显示,SOD1 运动皮层和脊髓腹侧角都出现了星形胶质细胞增生。SOD1 脊髓星形胶质细胞的活化形态与体积测量结果有关,后者显示这些细胞在高钾血症期间的肿胀程度降低。此外,我们还观察到SOD1脊髓腹角的ECS收缩程度较低。免疫组化分析随后证实,SOD1脊髓中Kir4.1通道的表达减少,这与体积调节的减弱相吻合。尽管发生了星形胶质细胞增生,但 SOD1 小鼠的皮质星形胶质细胞并没有出现肿胀或 Kir4.1 表达的变化,我们也没有发现 ECS 参数的显著变化。此外,脑脊液中的钾含量也没有偏离生理浓度。因此,我们获得的结果表明,类似 ALS 的病理变化会导致脊髓星形胶质细胞中与 Kir4.1 下调相关的钾摄取受损,但根据我们从大脑皮层获得的数据,功能受损似乎与形态状态无关。
{"title":"ALS-like pathology diminishes swelling of spinal astrocytes in the SOD1 animal model.","authors":"Tereza Filipi, Jana Tureckova, Ondrej Vanatko, Martina Chmelova, Monika Kubiskova, Natalia Sirotova, Stanislava Matejkova, Lydia Vargova, Miroslava Anderova","doi":"10.3389/fncel.2024.1472374","DOIUrl":"https://doi.org/10.3389/fncel.2024.1472374","url":null,"abstract":"<p><p>Astrocytes are crucial for the functioning of the nervous system as they maintain the ion homeostasis via volume regulation. Pathological states, such as amyotrophic lateral sclerosis (ALS), affect astrocytes and might even cause a loss of such functions. In this study, we examined astrocytic swelling/volume recovery in both the brain and spinal cord of the SOD1 animal model to determine the level of their impairment caused by the ALS-like pathology. Astrocyte volume changes were measured in acute brain or spinal cord slices during and after exposure to hyperkalemia. We then compared the results with alterations of extracellular space (ECS) diffusion parameters, morphological changes, expression of the Kir4.1 channel and the potassium concentration measured in the cerebrospinal fluid, to further disclose the link between potassium and astrocytes in the ALS-like pathology. Morphological analysis revealed astrogliosis in both the motor cortex and the ventral horns of the SOD1 spinal cord. The activated morphology of SOD1 spinal astrocytes was associated with the results from volume measurements, which showed decreased swelling of these cells during hyperkalemia. Furthermore, we observed lower shrinkage of ECS in the SOD1 spinal ventral horns. Immunohistochemical analysis then confirmed decreased expression of the Kir4.1 channel in the SOD1 spinal cord, which corresponded with the diminished volume regulation. Despite astrogliosis, cortical astrocytes in SOD1 mice did not show alterations in swelling nor changes in Kir4.1 expression, and we did not identify significant changes in ECS parameters. Moreover, the potassium level in the cerebrospinal fluid did not deviate from the physiological concentration. The results we obtained thus suggest that ALS-like pathology causes impaired potassium uptake associated with Kir4.1 downregulation in the spinal astrocytes, but based on our data from the cortex, the functional impairment seems to be independent of the morphological state.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11499153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142498013","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}
Pub Date : 2024-10-09eCollection Date: 2024-01-01DOI: 10.3389/fncel.2024.1406970
Simon Maksour, Rocio K Finol-Urdaneta, Amy J Hulme, Mauricio E Castro Cabral-da-Silva, Helena Targa Dias Anastacio, Rachelle Balez, Tracey Berg, Calista Turner, Sonia Sanz Muñoz, Martin Engel, Predrag Kalajdzic, Leszek Lisowski, Kuldip Sidhu, Perminder S Sachdev, Mirella Dottori, Lezanne Ooi
Alzheimer's disease (AD) is a devastating neurodegenerative condition that affects memory and cognition, characterized by neuronal loss and currently lacking a cure. Mutations in PSEN1 (Presenilin 1) are among the most common causes of early-onset familial AD (fAD). While changes in neuronal excitability are believed to be early indicators of AD progression, the link between PSEN1 mutations and neuronal excitability remains to be fully elucidated. This study examined iPSC-derived neurons (iNs) from fAD patients with PSEN1 mutations S290C or A246E, alongside CRISPR-corrected isogenic cell lines, to investigate early changes in excitability. Electrophysiological profiling revealed reduced excitability in both PSEN1 mutant iNs compared to their isogenic controls. Neurons bearing S290C and A246E mutations exhibited divergent passive membrane properties compared to isogenic controls, suggesting distinct effects of PSEN1 mutations on neuronal excitability. Additionally, both PSEN1 backgrounds exhibited higher current density of voltage-gated potassium (Kv) channels relative to their isogenic iNs, while displaying comparable voltage-gated sodium (Nav) channel current density. This suggests that the Nav/Kv imbalance contributes to impaired neuronal firing in fAD iNs. Deciphering these early cellular and molecular changes in AD is crucial for understanding disease pathogenesis.
阿尔茨海默病(AD)是一种影响记忆和认知的破坏性神经退行性疾病,以神经元缺失为特征,目前尚无治愈方法。PSEN1(Presenilin 1)基因突变是早发性家族性阿尔茨海默病(fAD)最常见的病因之一。虽然神经元兴奋性的变化被认为是AD进展的早期指标,但PSEN1突变与神经元兴奋性之间的联系仍有待全面阐明。本研究检测了来自PSEN1突变S290C或A246E的fAD患者的iPSC衍生神经元(iNs),以及经CRISPR校正的同源细胞系,以研究兴奋性的早期变化。电生理学分析表明,与同源对照组相比,PSEN1突变iNs的兴奋性都有所降低。与同源对照组相比,S290C 和 A246E 突变的神经元表现出不同的被动膜特性,这表明 PSEN1 突变对神经元兴奋性有不同的影响。此外,与同源 iNs 相比,两种 PSEN1 背景均表现出更高的电压门控钾(Kv)通道电流密度,而电压门控钠(Nav)通道电流密度却相当。这表明,Nav/Kv 的不平衡导致了 fAD iNs 神经元点燃功能受损。破译 AD 的这些早期细胞和分子变化对于了解疾病的发病机制至关重要。
{"title":"Alzheimer's disease induced neurons bearing <i>PSEN1</i> mutations exhibit reduced excitability.","authors":"Simon Maksour, Rocio K Finol-Urdaneta, Amy J Hulme, Mauricio E Castro Cabral-da-Silva, Helena Targa Dias Anastacio, Rachelle Balez, Tracey Berg, Calista Turner, Sonia Sanz Muñoz, Martin Engel, Predrag Kalajdzic, Leszek Lisowski, Kuldip Sidhu, Perminder S Sachdev, Mirella Dottori, Lezanne Ooi","doi":"10.3389/fncel.2024.1406970","DOIUrl":"https://doi.org/10.3389/fncel.2024.1406970","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a devastating neurodegenerative condition that affects memory and cognition, characterized by neuronal loss and currently lacking a cure. Mutations in <i>PSEN1</i> (Presenilin 1) are among the most common causes of early-onset familial AD (fAD). While changes in neuronal excitability are believed to be early indicators of AD progression, the link between <i>PSEN1</i> mutations and neuronal excitability remains to be fully elucidated. This study examined iPSC-derived neurons (iNs) from fAD patients with <i>PSEN1</i> mutations S290C or A246E, alongside CRISPR-corrected isogenic cell lines, to investigate early changes in excitability. Electrophysiological profiling revealed reduced excitability in both <i>PSEN1</i> mutant iNs compared to their isogenic controls. Neurons bearing S290C and A246E mutations exhibited divergent passive membrane properties compared to isogenic controls, suggesting distinct effects of <i>PSEN1</i> mutations on neuronal excitability. Additionally, both <i>PSEN1</i> backgrounds exhibited higher current density of voltage-gated potassium (Kv) channels relative to their isogenic iNs, while displaying comparable voltage-gated sodium (Nav) channel current density. This suggests that the Nav/Kv imbalance contributes to impaired neuronal firing in fAD iNs. Deciphering these early cellular and molecular changes in AD is crucial for understanding disease pathogenesis.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11497635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142498014","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}
Retinitis Pigmentosa (RP) is a heterogenous group of inherited disorder, and its progression not only affects the retina but also the primary visual cortex. This manifests imbalances in the excitatory and inhibitory neurotransmission. Here, we investigated if changes in cortical functioning is linked to alterations in GABAergic population of neurons and its two important subsets, somatostatin (SST) and parvalbumin (PV) neuron in rd1 model of retinal degeneration (RD). We demonstrate marked decrease in the proportion of SST neurons in different layers of cortex whereas PV neurons were less affected. Moreover, we found reduced expression of glutamatergic thalamic afferents (VGLUT2) due to lack of visual activity. These results suggest PV neurons are likely recruited by the cortical circuitry to increase the inhibitory drive and compensate the disrupted inhibition-excitation balance. However, reduced SST expression perhaps results in weakening of stimulus selectivity. Delineating their functional role during RD will provide insights for acquisition of high-resolution vision thereby improving current state of vision restoration.
{"title":"Deprivation of visual input alters specific subset of inhibitory neurons and affect thalamic afferent terminals in V1 of <i>rd1</i> mouse.","authors":"Kashish Parnami, Anushka Surana, Vineet Choudhary, Anwesha Bhattacharyya","doi":"10.3389/fncel.2024.1422613","DOIUrl":"https://doi.org/10.3389/fncel.2024.1422613","url":null,"abstract":"<p><p>Retinitis Pigmentosa (RP) is a heterogenous group of inherited disorder, and its progression not only affects the retina but also the primary visual cortex. This manifests imbalances in the excitatory and inhibitory neurotransmission. Here, we investigated if changes in cortical functioning is linked to alterations in GABAergic population of neurons and its two important subsets, somatostatin (SST) and parvalbumin (PV) neuron in <i>rd1</i> model of retinal degeneration (RD). We demonstrate marked decrease in the proportion of SST neurons in different layers of cortex whereas PV neurons were less affected. Moreover, we found reduced expression of glutamatergic thalamic afferents (VGLUT2) due to lack of visual activity. These results suggest PV neurons are likely recruited by the cortical circuitry to increase the inhibitory drive and compensate the disrupted inhibition-excitation balance. However, reduced SST expression perhaps results in weakening of stimulus selectivity. Delineating their functional role during RD will provide insights for acquisition of high-resolution vision thereby improving current state of vision restoration.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11496165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142498015","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}