Frontiers in Cellular Neuroscience最新文献

{"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":"18 ","pages":"1477989"},"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}

{"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⁺ 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.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"18 ","pages":"1465531"},"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}

{"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":"18 ","pages":"1472374"},"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}

{"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":"18 ","pages":"1406970"},"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}

{"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":"18 ","pages":"1422613"},"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}

{"title":"Retraction: Santacruzamate A Ameliorates AD-Like Pathology by Enhancing ER Stress Tolerance Through Regulating the Functions of KDELR and Mia40-ALR <i>in vivo</i> and <i>in vitro</i>.","authors":"","doi":"10.3389/fncel.2024.1505362","DOIUrl":"https://doi.org/10.3389/fncel.2024.1505362","url":null,"abstract":"<p><p>[This retracts the article DOI: 10.3389/fncel.2019.00061.].</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"18 ","pages":"1505362"},"PeriodicalIF":4.2,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11494726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142516361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of maternal anti-inflammatory drugs on surgical anesthesia-induced neuroinflammation and cognitive impairment in offspring mice.","authors":"Dongdong Chai, Hong Jiang, Hua Liu","doi":"10.3389/fncel.2024.1481630","DOIUrl":"https://doi.org/10.3389/fncel.2024.1481630","url":null,"abstract":"<p><strong>Background: </strong>The impact of maternal surgery combined with general anesthesia on neuroinflammation and the development of learning and memory impairment in offspring remains unclear. This study utilized a pathogen-free laparotomy model to investigate these changes during the second trimester, as well as their response to anti-inflammatory therapy.</p><p><strong>Methods: </strong>C57BL/6 pregnant mice at the 14.5-day embryo stage (E 14.5) were either exposed to sevoflurane anesthesia alone or underwent laparotomy procedure. The neuroinflammatory response was evaluated at 7, 14, 21, and 28 days postnatal (P7, P14, P21, P28). Tau phosphorylation and cognitive ability were assessed at P28 and P30, respectively. The impact of perioperative administration of ibuprofen (60 mg/kg) on these aforementioned changes was subsequently evaluated.</p><p><strong>Results: </strong>In the laparotomy group, levels of inflammatory factors (IL-4, IL-8, IL-17A, TGF-β, M-CSF, CCL2) in the brains of offspring mice, including the cerebral cortex and hippocampus, remained consistently elevated from P7 to P28. At P14, while the majority of inflammatory cytokine has no statistical difference, there was still a significant reactivation of inflammatory cytokines observed in the frontal cortex and hippocampus at P28. Furthermore, abnormal phosphorylation of tau and deficits in learning and memory were observed at P28 and P30. Administration of perioperative ibuprofen led to improvements in cognitive performance, reduction of systemic inflammation, and inhibiting abnormal phosphorylation of tau in the frontal cortex and hippocampus.</p><p><strong>Conclusion: </strong>Our findings indicate that cognitive dysfunction is correlated with elevated levels of inflammatory cytokines and tau phosphorylation. Cognitive impairment and tau phosphorylation after laparotomy can persist at least until P28. Anti-inflammatory medications have been shown to enhance cognitive function by rapidly reducing inflammation in the brain, while also impacting neurological changes. This discovery may have implications for the development of treatment strategies aimed at managing cognitive impairment in post-operative patients.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"18 ","pages":"1481630"},"PeriodicalIF":4.2,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11493650/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142498025","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":"Organoid intelligence for developmental neurotoxicity testing.","authors":"Dowlette-Mary Alam El Din, Jeongwon Shin, Alexandra Lysinger, Matthew J Roos, Erik C Johnson, Timothy J Shafer, Thomas Hartung, Lena Smirnova","doi":"10.3389/fncel.2024.1480845","DOIUrl":"https://doi.org/10.3389/fncel.2024.1480845","url":null,"abstract":"<p><p>The increasing prevalence of neurodevelopmental disorders has highlighted the need for improved testing methods to determine developmental neurotoxicity (DNT) hazard for thousands of chemicals. This paper proposes the integration of organoid intelligence (OI); leveraging brain organoids to study neuroplasticity <i>in vitro,</i> into the DNT testing paradigm. OI brings a new approach to measure the impacts of xenobiotics on plasticity mechanisms - a critical biological process that is not adequately covered in current DNT <i>in vitro</i> assays. Finally, the integration of artificial intelligence (AI) techniques will further facilitate the analysis of complex brain organoid data to study these plasticity mechanisms.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"18 ","pages":"1480845"},"PeriodicalIF":4.2,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11493634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142516360","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":"Mathematical models of C-type and N-type inactivating heteromeric voltage gated potassium channels.","authors":"Kees McGahan, James Keener","doi":"10.3389/fncel.2024.1418125","DOIUrl":"https://doi.org/10.3389/fncel.2024.1418125","url":null,"abstract":"<p><p>Voltage gated potassium channels can be composed of either four identical, or different, pore-forming protein subunits. While the voltage gated channels with identical subunits have been extensively studied both physiologically and mathematically, those with multiple subunit types, termed heteromeric channels, have not been. Here we construct, and explore the predictive outputs of, mechanistic models for heteromeric voltage gated potassium channels that possess either N-type or C-type inactivation kinetics. For both types of inactivation, we first build Markov models of four identical pore-forming inactivating subunits. Combining this with previous results regarding non-inactivating heteromeric channels, we are able to define models for heteromeric channels containing both non-inactivating and inactivating subunits of any ratio. We simulate each model through three unique voltage clamp protocols to identify steady state properties. In doing so, we generate predictions about the impact of adding additional inactivating subunits on a total channel's kinetics. We show that while N-type inactivating subunits appear to have a non-linear impact on the level of inactivation the channel experiences, the effect of C-type inactivating subunits is almost linear. Finally, to combat the computational issues of working with a large number of state variables we define model reductions for both types of heteromeric channels. For the N-type heteromers we derive a quasi-steady-state approximation and indicate where the approximation is appropriate. With the C-type heteromers we are able to write an explicit model reduction bringing models of greater than 10 dimensions down to 2.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"18 ","pages":"1418125"},"PeriodicalIF":4.2,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11493646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142498024","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":"Therapeutic potential of mesenchymal stem cell-derived exosomes and miRNAs in neuronal regeneration and rejuvenation in neurological disorders: a mini review.","authors":"Aria Salehpour, Zahra Karimi, Mokhtar Ghasemi Zadeh, Mohammadreza Afshar, Ali Kameli, Fatemeh Mooseli, Masoud Zare, Alireza Afshar","doi":"10.3389/fncel.2024.1427525","DOIUrl":"10.3389/fncel.2024.1427525","url":null,"abstract":"<p><p>Mesenchymal stem cells (MSCs) have gained considerable attention in the field of regenerative medicine due to their ability to secrete small extracellular vesicles (EVs) known as exosomes. This review delves into the various biological activities of MSCs and the cell interactions enabled by these exosomes, with a focus on their potential for neuronal regeneration and the treatment of neurological disorders. We scrutinize findings from multiple studies that underscore the neuroprotective and neuro-regenerative effects of exosomes derived from MSCs, illuminating their mechanisms of action and therapeutic applications. This review thoroughly investigates all related pathways, miRNAs, and factors to suggest potential strategies for enhancing therapy for neurological disorders using exosomes and miRNAs, and for boosting neuronal regeneration.</p>","PeriodicalId":12432,"journal":{"name":"Frontiers in Cellular Neuroscience","volume":"18 ","pages":"1427525"},"PeriodicalIF":4.2,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11486650/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461926","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}