23 results on '"Katrin Linda"'
Search Results
2. m.3243A > G-Induced Mitochondrial Dysfunction Impairs Human Neuronal Development and Reduces Neuronal Network Activity and Synchronicity
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Teun M. Klein Gunnewiek, Eline J.H. Van Hugte, Monica Frega, Gemma Solé Guardia, Katharina Foreman, Daan Panneman, Britt Mossink, Katrin Linda, Jason M. Keller, Dirk Schubert, David Cassiman, Richard Rodenburg, Noemi Vidal Folch, Devin Oglesbee, Ester Perales-Clemente, Timothy J. Nelson, Eva Morava, Nael Nadif Kasri, and Tamas Kozicz
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Biology (General) ,QH301-705.5 - Abstract
Summary: Epilepsy, intellectual and cortical sensory deficits, and psychiatric manifestations are the most frequent manifestations of mitochondrial diseases. How mitochondrial dysfunction affects neural structure and function remains elusive, mostly because of a lack of proper in vitro neuronal model systems with mitochondrial dysfunction. Leveraging induced pluripotent stem cell technology, we differentiated excitatory cortical neurons (iNeurons) with normal (low heteroplasmy) and impaired (high heteroplasmy) mitochondrial function on an isogenic nuclear DNA background from patients with the common pathogenic m.3243A > G variant of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). iNeurons with high heteroplasmy exhibited mitochondrial dysfunction, delayed neural maturation, reduced dendritic complexity, and fewer excitatory synapses. Micro-electrode array recordings of neuronal networks displayed reduced network activity and decreased synchronous network bursting. Impaired neuronal energy metabolism and compromised structural and functional integrity of neurons and neural networks could be the primary drivers of increased susceptibility to neuropsychiatric manifestations of mitochondrial disease. : Using human-inducible-pluripotent-stem-cell-derived neurons with high levels of m.3243A > G heteroplasmy, Klein Gunnewiek et al. show neuron-specific mitochondrial dysfunction as well as structural and functional impairments ranging from reduced dendritic complexity and fewer synapses and mitochondria to reduced neuronal activity and impaired network synchronicity. Keywords: MELAS, mitochondrial disease, mitochondria, neuron, induced pluripotent stem cells, network activity, neurodevelopment, micro-electrode array, m.3243A > G
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- 2020
- Full Text
- View/download PDF
3. Distinct Pathogenic Genes Causing Intellectual Disability and Autism Exhibit a Common Neuronal Network Hyperactivity Phenotype
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Monica Frega, Martijn Selten, Britt Mossink, Jason M. Keller, Katrin Linda, Rebecca Moerschen, Jieqiong Qu, Pierre Koerner, Sophie Jansen, Astrid Oudakker, Tjitske Kleefstra, Hans van Bokhoven, Huiqing Zhou, Dirk Schubert, and Nael Nadif Kasri
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Biology (General) ,QH301-705.5 - Abstract
Summary: Pathogenic mutations in either one of the epigenetic modifiers EHMT1, MBD5, MLL3, or SMARCB1 have been identified to be causative for Kleefstra syndrome spectrum (KSS), a neurodevelopmental disorder with clinical features of both intellectual disability (ID) and autism spectrum disorder (ASD). To understand how these variants lead to the phenotypic convergence in KSS, we employ a loss-of-function approach to assess neuronal network development at the molecular, single-cell, and network activity level. KSS-gene-deficient neuronal networks all develop into hyperactive networks with altered network organization and excitatory-inhibitory balance. Interestingly, even though transcriptional data reveal distinct regulatory mechanisms, KSS target genes share similar functions in regulating neuronal excitability and synaptic function, several of which are associated with ID and ASD. Our results show that KSS genes mainly converge at the level of neuronal network communication, providing insights into the pathophysiology of KSS and phenotypically congruent disorders. : Frega et al. show that mutations in functionally distinct genes leading to Kleefstra syndrome converge at the molecular, cellular, and neuronal network levels. KSS gene deficiency leads to hyperactive neuronal network communication and altered excitatory-inhibitory balance. Common biological pathways related to ion-channel expression and synaptic communication underlie this functional convergence. Keywords: Kleefstra syndrome spectrum, autism, intellectual disability, EHMT1, neurodevelopmental disorder, neuronal networks, micro-electrode arrays
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- 2020
- Full Text
- View/download PDF
4. Mouse models of 17q21.31 microdeletion and microduplication syndromes highlight the importance of Kansl1 for cognition.
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Thomas Arbogast, Giovanni Iacono, Claire Chevalier, Nurudeen O Afinowi, Xander Houbaert, Matthijs C van Eede, Christine Laliberte, Marie-Christine Birling, Katrin Linda, Hamid Meziane, Mohammed Selloum, Tania Sorg, Nael Nadif Kasri, David A Koolen, Henk G Stunnenberg, R Mark Henkelman, Maksym Kopanitsa, Yann Humeau, Bert B A De Vries, and Yann Herault
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Genetics ,QH426-470 - Abstract
Koolen-de Vries syndrome (KdVS) is a multi-system disorder characterized by intellectual disability, friendly behavior, and congenital malformations. The syndrome is caused either by microdeletions in the 17q21.31 chromosomal region or by variants in the KANSL1 gene. The reciprocal 17q21.31 microduplication syndrome is associated with psychomotor delay, and reduced social interaction. To investigate the pathophysiology of 17q21.31 microdeletion and microduplication syndromes, we generated three mouse models: 1) the deletion (Del/+); or 2) the reciprocal duplication (Dup/+) of the 17q21.31 syntenic region; and 3) a heterozygous Kansl1 (Kans1+/-) model. We found altered weight, general activity, social behaviors, object recognition, and fear conditioning memory associated with craniofacial and brain structural changes observed in both Del/+ and Dup/+ animals. By investigating hippocampus function, we showed synaptic transmission defects in Del/+ and Dup/+ mice. Mutant mice with a heterozygous loss-of-function mutation in Kansl1 displayed similar behavioral and anatomical phenotypes compared to Del/+ mice with the exception of sociability phenotypes. Genes controlling chromatin organization, synaptic transmission and neurogenesis were upregulated in the hippocampus of Del/+ and Kansl1+/- animals. Our results demonstrate the implication of KANSL1 in the manifestation of KdVS phenotypes and extend substantially our knowledge about biological processes affected by these mutations. Clear differences in social behavior and gene expression profiles between Del/+ and Kansl1+/- mice suggested potential roles of other genes affected by the 17q21.31 deletion. Together, these novel mouse models provide new genetic tools valuable for the development of therapeutic approaches.
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- 2017
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5. Cadherin-13 is a critical regulator of GABAergic modulation in human stem-cell-derived neuronal networks
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Teun M. Klein Gunnewiek, Maria Rosaria Vitale, Brooke L. Latour, Sophie Jansen, Nael Nadif Kasri, Jon-Ruben van Rhijn, Dirk Schubert, Eline J.H. van Hugte, Martijn Selten, Jitske Bak, Anouk H.A. Verboven, Alessia Anania, Ilse M. van der Werf, Katrin Linda, Klaus-Peter Lesch, Johanna E. M. Zöller, Hans van Bokhoven, Chantal Schoenmaker, Moritz Negwer, Britt Mossink, Monica Frega, Jason M. Keller, Shan Wang, Astrid R. Oudakker, Clinical Neurophysiology, TechMed Centre, Psychiatrie & Neuropsychologie, and RS: MHeNs - R3 - Neuroscience
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INTERNEURONS ,0301 basic medicine ,Integrins ,Induced Pluripotent Stem Cells ,Population ,INHIBITION ,Regulator ,ADHESION ,Inhibitory postsynaptic potential ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Glutamatergic ,0302 clinical medicine ,Humans ,TRANSCRIPTION FACTOR ,GABAergic Neurons ,GENOME-WIDE ASSOCIATION ,FUNCTIONAL MATURATION ,AUTISM ,Induced pluripotent stem cell ,education ,Molecular Biology ,education.field_of_study ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,RECEPTOR ,biology ,IMBALANCE ,Cadherins ,Psychiatry and Mental health ,Parvalbumins ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,030104 developmental biology ,Synapses ,T-CADHERIN ,biology.protein ,GABAergic ,Stem cell ,Neuroscience ,030217 neurology & neurosurgery ,Parvalbumin - Abstract
Activity in the healthy brain relies on a concerted interplay of excitation (E) and inhibition (I) via balanced synaptic communication between glutamatergic and GABAergic neurons. A growing number of studies imply that disruption of this E/I balance is a commonality in many brain disorders; however, obtaining mechanistic insight into these disruptions, with translational value for the patient, has typically been hampered by methodological limitations. Cadherin-13 (CDH13) has been associated with autism and attention-deficit/hyperactivity disorder. CDH13 localizes at inhibitory presynapses, specifically of parvalbumin (PV) and somatostatin (SST) expressing GABAergic neurons. However, the mechanism by which CDH13 regulates the function of inhibitory synapses in human neurons remains unknown. Starting from human-induced pluripotent stem cells, we established a robust method to generate a homogenous population of SST and MEF2C (PV-precursor marker protein) expressing GABAergic neurons (iGABA) in vitro, and co-cultured these with glutamatergic neurons at defined E/I ratios on micro-electrode arrays. We identified functional network parameters that are most reliably affected by GABAergic modulation as such, and through alterations of E/I balance by reduced expression of CDH13 in iGABAs. We found that CDH13 deficiency in iGABAs decreased E/I balance by means of increased inhibition. Moreover, CDH13 interacts with Integrin-β1 and Integrin-β3, which play opposite roles in the regulation of inhibitory synaptic strength via this interaction. Taken together, this model allows for standardized investigation of the E/I balance in a human neuronal background and can be deployed to dissect the cell-type-specific contribution of disease genes to the E/I balance.
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- 2022
6. Human neuronal networks on micro-electrode arrays are a highly robust tool to study disease-specific genotype-phenotype correlations in vitro
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Giulia Parodi, Teun M. Klein Gunnewiek, Nael Nadif Kasri, Tjitske Kleefstra, Monica Frega, Hans van Bokhoven, Anouk H.A. Verboven, Katrin Linda, Dirk Schubert, Tamas Kozicz, Chantal Schoenmaker, Eline J.H. van Hugte, B. Mossink, Clinical Neurophysiology, and TechMed Centre
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Disease specific ,neuronal network activity ,UT-Gold-D ,Computer science ,Cell Culture Techniques ,Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13] ,Action Potentials ,Biology ,Biochemistry ,Article ,Mice ,Lab-On-A-Chip Devices ,Micro electrode ,Genetics ,Biological neural network ,Animals ,Humans ,Premovement neuronal activity ,Induced pluripotent stem cell ,Electrodes ,neuronal differentiation ,Genotype-Phenotype Correlations ,Cells, Cultured ,Genetic Association Studies ,Neurons ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Drug discovery ,food and beverages ,Robustness (evolution) ,Cell Differentiation ,Cell Biology ,Microarray Analysis ,Phenotype ,human induced pluripotent stem cells ,micro-electrode arrays ,Nerve Net ,Neuroscience ,Developmental Biology - Abstract
Summary Micro-electrode arrays (MEAs) are increasingly used to characterize neuronal network activity of human induced pluripotent stem cell (hiPSC)-derived neurons. Despite their gain in popularity, MEA recordings from hiPSC-derived neuronal networks are not always used to their full potential in respect to experimental design, execution, and data analysis. Therefore, we benchmarked the robustness of MEA-derived neuronal activity patterns from ten healthy individual control lines, and uncover comparable network phenotypes. To achieve standardization, we provide recommendations on experimental design and analysis. With such standardization, MEAs can be used as a reliable platform to distinguish (disease-specific) network phenotypes. In conclusion, we show that MEAs are a powerful and robust tool to uncover functional neuronal network phenotypes from hiPSC-derived neuronal networks, and provide an important resource to advance the hiPSC field toward the use of MEAs for disease phenotyping and drug discovery., Highlights • MEAs are a robust tool to model neuronal network functioning • Neuronal networks from different healthy donors show comparable network activity • MEAs are able to distinguish disease-specific neuronal network phenotypes • We provide recommendations to standardize neuronal network recordings on MEA, In this article, Mossink and colleagues demonstrate that micro-electrode arrays (MEAs) are a highly robust tool to uncover genotype/phenotype interactions in hiPSC-derived excitatory neuronal networks, and provide an important resource for the design, execution, and analysis of hiPSC-derived neuronal networks studies on MEA.
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- 2021
7. Imbalanced autophagy causes synaptic deficits in a human model for neurodevelopmental disorders
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Marina P Hommersom, Chantal Schoenmaker, Astrid R. Oudakker, Katrin Linda, Lynn Devilee, Elly Lewerissa, Nael Nadif Kasri, Anouk H.A. Verboven, Bert B.A. de Vries, Michele Gabriele, Giuseppe Testa, David A. Koolen, Hans van Bokhoven, Monica Frega, Teun M. Klein Gunnewiek, Edda Ulferts, Dirk Schubert, Clinical Neurophysiology, and TechMed Centre
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Autophagosome ,iPSCs ,Chromatin remodeling ,Epigenesis, Genetic ,Superoxide Dismutase-1 ,Sequestosome 1 ,Koolen-de Vries syndrome ,Intellectual Disability ,Lysosome ,medicine ,Autophagy ,neuronal development ,Humans ,Abnormalities, Multiple ,education ,synaptic function ,Molecular Biology ,Mechanistic target of rapamycin ,PI3K/AKT/mTOR pathway ,Sirolimus ,chemistry.chemical_classification ,reactive oxygen species ,Reactive oxygen species ,education.field_of_study ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,biology ,Lysine ,TOR Serine-Threonine Kinases ,MTOR ,Autophagosomes ,Cell Biology ,Cell biology ,medicine.anatomical_structure ,chemistry ,biology.protein ,Chromosome Deletion ,Lysosomes ,Chromosomes, Human, Pair 17 - Abstract
Contains fulltext : 248864.pdf (Publisher’s version ) (Open Access) Macroautophagy (hereafter referred to as autophagy) is a finely tuned process of programmed degradation and recycling of proteins and cellular components, which is crucial in neuronal function and synaptic integrity. Mounting evidence implicates chromatin remodeling in fine-tuning autophagy pathways. However, this epigenetic regulation is poorly understood in neurons. Here, we investigate the role in autophagy of KANSL1, a member of the nonspecific lethal complex, which acetylates histone H4 on lysine 16 (H4K16ac) to facilitate transcriptional activation. Loss-of-function of KANSL1 is strongly associated with the neurodevelopmental disorder Koolen-de Vries Syndrome (KdVS). Starting from KANSL1-deficient human induced-pluripotent stem cells, both from KdVS patients and genome-edited lines, we identified SOD1 (superoxide dismutase 1), an antioxidant enzyme, to be significantly decreased, leading to a subsequent increase in oxidative stress and autophagosome accumulation. In KANSL1-deficient neurons, autophagosome accumulation at excitatory synapses resulted in reduced synaptic density, reduced GRIA/AMPA receptor-mediated transmission and impaired neuronal network activity. Furthermore, we found that increased oxidative stress-mediated autophagosome accumulation leads to increased MTOR activation and decreased lysosome function, further preventing the clearing of autophagosomes. Finally, by pharmacologically reducing oxidative stress, we could rescue the aberrant autophagosome formation as well as synaptic and neuronal network activity in KANSL1-deficient neurons. Our findings thus point toward an important relation between oxidative stress-induced autophagy and synapse function, and demonstrate the importance of H4K16ac-mediated changes in chromatin structure to balance reactive oxygen species- and MTOR-dependent autophagy.Abbreviations: APO: apocynin; ATG: autophagy related; BAF: bafilomycin A(1); BSO: buthionine sulfoximine; CV: coefficient of variation; DIV: days in vitro; H4K16ac: histone 4 lysine 16 acetylation; iPSC: induced-pluripotent stem cell; KANSL1: KAT8 regulatory NSL complex subunit 1; KdVS: Koolen-de Vries Syndrome; LAMP1: lysosomal associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MEA: micro-electrode array; MTOR: mechanistic target of rapamycin kinase; NSL complex: nonspecific lethal complex; 8-oxo-dG: 8-hydroxydesoxyguanosine; RAP: rapamycin; ROS: reactive oxygen species; sEPSCs: spontaneous excitatory postsynaptic currents; SOD1: superoxide dismutase 1; SQSTM1/p62: sequestosome 1; SYN: synapsin; WRT: wortmannin.
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- 2022
8. Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder
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Daniel L. Polla, Sirous Zeinali, Nina A. Demina, Majid Yavarian, Stylianos E. Antonarakis, Sandra von Hardenberg, Saima Riazuddin, Filomena Pirozzi, Sven Hethey, Zubair M. Ahmed, Leah Fleming, Jacek Pilch, John Condie, Vasilina S. Sergeeva, Mohammad Ali Faghihi, Nael Nadif Kasri, Shima Bahramjahan, Neelam Fatima, Periklis Makrythanasis, Muhammad Ansar, Alena L. Chukhrova, Anke K. Bergmann, Hanka Venselaar, Mohsin Shahzad, Arjan P.M. de Brouwer, Mohammad Ali Farazi Fard, Hans van Bokhoven, Ghayda M. Mirzaa, Mohammad-Sadegh Fallah, Hennie T. Brüggenwirth, Olga Levchenko, Laura Donker Kaat, Afsaneh Taghipour Sheshdeh, Pooneh Nikuei, Amira Masri, Mureed Hussain, Agnieszka Pollak, Federico Santoni, Katrin Linda, Alexander Lavrov, Fareeha Fatima, Ebrahim Eftekhar, Hanan Hamamy, Gaia Ruggeri, Sheikh Riazuddin, Zahra Tabatabaei, Janneke H M Schuurs-Hoeijmakers, Rafał Płoski, Parham Habibzadeh, Mohammad Silawi, and Clinical Genetics
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0301 basic medicine ,030105 genetics & heredity ,Biology ,Article ,03 medical and health sciences ,Neurodevelopmental disorder ,Intellectual Disability ,Gene expression ,Exome Sequencing ,medicine ,Humans ,Induced pluripotent stem cell ,Gene ,Genetics (clinical) ,Exome sequencing ,Genetics ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Human brain ,medicine.disease ,Hypotonia ,Pedigree ,Reverse transcription polymerase chain reaction ,030104 developmental biology ,medicine.anatomical_structure ,Neurodevelopmental Disorders ,medicine.symptom ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] - Abstract
Purpose: To elucidate the novel molecular cause in families with a new autosomal recessive neurodevelopmental disorder. Methods: A combination of exome sequencing and gene matching tools was used to identify pathogenic variants in 17 individuals. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) and subcellular localization studies were used to characterize gene expression profile and localization. Results: Biallelic variants in the TMEM222 gene were identified in 17 individuals from nine unrelated families, presenting with intellectual disability and variable other features, such as aggressive behavior, shy character, body tremors, decreased muscle mass in the lower extremities, and mild hypotonia. We found relatively high TMEM222 expression levels in the human brain, especially in the parietal and occipital cortex. Additionally, subcellular localization analysis in human neurons derived from induced pluripotent stem cells (iPSCs) revealed that TMEM222 localizes to early endosomes in the synapses of mature iPSC-derived neurons. Conclusion: Our findings support a role for TMEM222 in brain development and function and adds variants in the gene TMEM222 as a novel underlying cause of an autosomal recessive neurodevelopmental disorder.
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- 2021
9. KANSL1 Deficiency Causes Neuronal Dysfunction by Oxidative Stress-Induced Autophagy
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Lynn Devilee, Giuseppe Testa, Dirk Schubert, EIly I. Lewerissa, Nael Nadif Kasri, Monica Frega, Edda Ulferts, Michele Gabriele, Hans van Bokhoven, Katrin Linda, Chantal Schoenmaker, Teun M. Klein Gunnewiek, Anouk H.A. Verboven, Bert B.A. de Vries, David A. Koolen, and Astrid R. Oudakker
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Autophagosome ,chemistry.chemical_classification ,Reactive oxygen species ,biology ,Chemistry ,Autophagy ,medicine.disease_cause ,Cell biology ,Synapse ,Superoxide dismutase ,medicine.anatomical_structure ,Lysosome ,medicine ,biology.protein ,Oxidative stress ,PI3K/AKT/mTOR pathway - Abstract
Autophagy is a finely tuned process of programmed degradation and recycling of proteins and cellular components, which is crucial in neuronal function and synaptic integrity. Mounting evidence implicates chromatin remodelling in fine-tuning autophagy pathways. However, this epigenetic regulation is poorly understood in neurons. Here, we investigate the role in autophagy of KANSL1, a member of the nonspecific lethal complex, which acetylates histone H4 on lysine 16 (H4K16ac) to facilitate transcriptional activation. Loss-of-function of KANSL1 is strongly associated with the neurodevelopmental disorder Koolen-de Vries Syndrome (KdVS).Starting from KANSL1-deficient human induced-pluripotent stem cells, both from KdVS patients and genome-edited lines, we identified superoxide dismutase 1, an antioxidant enzyme, to be significantly decreased, leading to a subsequent increase in oxidative stress and autophagosome accumulation. In KANSL1-deficient neurons, autophagosome accumulation at excitatory synapses resulted in reduced synaptic density, reduced AMPA receptor-mediated transmission and impaired neuronal network activity. Furthermore, we found that increased oxidative stress-mediated autophagosome accumulation leads to increased mTOR activation and decreased lysosome function, further preventing the clearing of autophagosomes. Finally, by pharmacologically reducing oxidative stress, we could rescue the aberrant autophagosome formation as well as synaptic and neuronal network activity in KANSL1-deficient neurons. Our findings thus point towards an important relation between oxidative stress-induced autophagy and synapse function, and demonstrate the importance of H4K16ac-mediated changes in chromatin structure to balance reactive oxygen species- and mTOR-dependent autophagy.
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- 2020
10. Cadherin-13 is a critical regulator of GABAergic modulation in human stem cell derived neuronal networks
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Alessia Anania, Sophie Jansen, Jon-Ruben van Rhijn, Hans van Bokhoven, Nael Nadif Kasri, Katrin Linda, Britt Mossink, Anouk H.A. Verboven, Jitske Bak, Dirk Schubert, Teun M. Klein Gunnewiek, Shan Wang, Eline J.H. van Hugte, Jason M. Keller, Monica Frega, Astrid R. Oudakker, Martijn Selten, and Chantal Schoenmaker
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education.field_of_study ,Glutamatergic ,biology ,Cadherin ,Population ,biology.protein ,Regulator ,GABAergic ,Stem cell ,Inhibitory postsynaptic potential ,education ,Neuroscience ,Parvalbumin - Abstract
SummaryActivity in the healthy brain relies on concerted interplay of excitation (E) and inhibition (I) via balanced synaptic communication between glutamatergic and GABAergic neurons. A growing number of studies imply that disruption of this E/I balance is a commonality in many brain disorders, however, obtaining mechanistic insight into these disruptions, with translational value for the human patient, has typically been hampered by methodological limitations.Cadherin-13(CDH13) has strongly been associated to attention-deficit/hyperactivity disorder and comorbid disorders such as autism and schizophrenia. CDH13 localises at inhibitory presynapses, specifically of parvalbumin (PV) and somatostatin (SST) expressing GABAergic neurons. However, the mechanism by which CDH13 regulates the function of inhibitory synapses in human neurons remains unknown. Starting from human induced pluripotent stem cells, we established a robust method to generate a homogenous population of SST and PV expressing GABAergic neurons (iGABA)in vitro, and co-cultured these with glutamatergic neurons at defined E/I ratios on micro-electrode arrays. We identified functional network parameters that are most reliably affected by GABAergic modulation as such, and through alterations of E/I balance by reduced expression of CDH13 in iGABAs. We found that CDH13-deficiency in iGABAs decreased E/I balance by means of increased inhibition. Moreover, CDH13 interacts with Integrin-β1 and Integrin-β3, which play opposite roles in the regulation of inhibitory synaptic strength via this interaction. Taken together, this model allows for standardized investigation of the E/I balance in a human neuronal background and can be deployed to dissect the cell-type specific contribution of disease genes to the E/I balance.
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- 2020
- Full Text
- View/download PDF
11. m.3243A > G-Induced Mitochondrial Dysfunction Impairs Human Neuronal Development and Reduces Neuronal Network Activity and Synchronicity
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Timothy J. Nelson, Noemi Vidal Folch, David Cassiman, Britt Mossink, Dirk Schubert, Monica Frega, Daan M. Panneman, Tamas Kozicz, Ester Perales-Clemente, Eva Morava, Eline J.H. van Hugte, Nael Nadif Kasri, Jason M. Keller, Katharina Foreman, Devin Oglesbee, Gemma Solé Guardia, Katrin Linda, Richard J. Rodenburg, T. M. Klein Gunnewiek, and Clinical Neurophysiology
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0301 basic medicine ,Mitochondrial encephalomyopathy ,Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1] ,induced pluripotent stem cells ,Mitochondrial disease ,Stress-related disorders Donders Center for Medical Neuroscience [Radboudumc 13] ,Mitochondrion ,Biology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Bursting ,All institutes and research themes of the Radboud University Medical Center ,0302 clinical medicine ,micro-electrode array ,medicine ,Biological neural network ,Animals ,Humans ,Rats, Wistar ,lcsh:QH301-705.5 ,Neurons ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,neurodevelopment ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,Cell Differentiation ,+G%22">m.3243A > G ,medicine.disease ,network activity ,Heteroplasmy ,neuron ,Rats ,mitochondria ,mitochondrial disease ,030104 developmental biology ,medicine.anatomical_structure ,lcsh:Biology (General) ,Lactic acidosis ,MELAS ,Neuron ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Summary: Epilepsy, intellectual and cortical sensory deficits, and psychiatric manifestations are the most frequent manifestations of mitochondrial diseases. How mitochondrial dysfunction affects neural structure and function remains elusive, mostly because of a lack of proper in vitro neuronal model systems with mitochondrial dysfunction. Leveraging induced pluripotent stem cell technology, we differentiated excitatory cortical neurons (iNeurons) with normal (low heteroplasmy) and impaired (high heteroplasmy) mitochondrial function on an isogenic nuclear DNA background from patients with the common pathogenic m.3243A > G variant of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). iNeurons with high heteroplasmy exhibited mitochondrial dysfunction, delayed neural maturation, reduced dendritic complexity, and fewer excitatory synapses. Micro-electrode array recordings of neuronal networks displayed reduced network activity and decreased synchronous network bursting. Impaired neuronal energy metabolism and compromised structural and functional integrity of neurons and neural networks could be the primary drivers of increased susceptibility to neuropsychiatric manifestations of mitochondrial disease. : Using human-inducible-pluripotent-stem-cell-derived neurons with high levels of m.3243A > G heteroplasmy, Klein Gunnewiek et al. show neuron-specific mitochondrial dysfunction as well as structural and functional impairments ranging from reduced dendritic complexity and fewer synapses and mitochondria to reduced neuronal activity and impaired network synchronicity. Keywords: MELAS, mitochondrial disease, mitochondria, neuron, induced pluripotent stem cells, network activity, neurodevelopment, micro-electrode array, m.3243A > G
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- 2020
12. Mitochondrial dysfunction impairs human neuronal development and reduces neuronal network activity and synchronicity
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Nael Nadif Kasri, David Cassiman, Daan M. Panneman, T. M. Klein Gunnewiek, Gemma Solé Guardia, Katrin Linda, Eva Morava, Timothy J. Nelson, Jason M. Keller, Eline J.H. van Hugte, Dirk Schubert, Katharina Foreman, Tamas Kozicz, Britt Mossink, Monica Frega, Richard J. Rodenburg, and Ester Perales-Clemente
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Mitochondrial encephalomyopathy ,Bursting ,medicine.anatomical_structure ,Lactic acidosis ,Mitochondrial disease ,medicine ,Biological neural network ,Neuron ,Mitochondrion ,Biology ,medicine.disease ,Neuroscience ,Heteroplasmy - Abstract
SummaryEpilepsy, intellectual and cortical sensory deficits and psychiatric manifestations are among the most frequent manifestations of mitochondrial diseases. Yet, how mitochondrial dysfunction affects neural structure and function remains largely elusive. This is mostly due to the lack of a properin vitrotranslational neuronal model system(s) with impaired energy metabolism. Leveraging the induced pluripotent stem cell technology, from a cohort of patients with the common pathogenic m.3243A>G variant of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), we differentiated excitatory cortical neurons (iNeurons) with normal (low heteroplasmy) and impaired (high heteroplasmy) mitochondrial function on an isogenic nuclear DNA background. iNeurons with high levels of heteroplasmy exhibited mitochondrial dysfunction, delayed neural maturation, reduced dendritic complexity and fewer functional excitatory synapses. Micro-electrode array recordings of neuronal networks with high heteroplasmy displayed reduced network activity and decreased synchronous network bursting. The impaired neural energy metabolism of iNeurons compromising the structural and functional integrity of neurons and neural networks, could be the primary driver of increased susceptibility to neuropsychiatric manifestations of mitochondrial disease.
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- 2019
13. Neuronal network dysfunction in a human model for Kleefstra syndrome mediated by enhanced NMDAR signaling
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Monica Frega, Moritz Negwer, Teun M. Klein Gunnewiek, Güvem Gümüş-Akay, Astrid R. Oudakker, Katharina Foreman, Britt Mossink, Jason M. Keller, Nine Kompier, Nael Nadif Kasri, Willem M.R. van den Akker, Huiqing Zhou, Jon-Ruben van Rhijn, Tjitske Kleefstra, Dirk Schubert, Hans van Bokhoven, Chantal Schoenmaker, and Katrin Linda
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GRIN1 ,Biology ,medicine.disease ,EHMT1 ,Neurodevelopmental disorder ,nervous system ,Histone methyltransferase ,Biological neural network ,medicine ,biology.protein ,Epigenetics ,Induced pluripotent stem cell ,Neuroscience ,Kleefstra Syndrome - Abstract
Epigenetic regulation of gene transcription plays a critical role in neural network development and in the etiology of Intellectual Disability (ID) and Autism Spectrum Disorder (ASD). However, little is known about the mechanisms by which epigenetic dysregulation leads to neural network defects. Kleefstra syndrome (KS), caused by mutation in the histone methyltransferase EHMT1, is a neurodevelopmental disorder with the clinical features of both ID and ASD. To study the impact of decreased EHMT1 function in human cells, we generated excitatory cortical neurons from induced pluripotent stem (iPS) cells derived from KS patients. In addition, we created an isogenic set by genetically editing healthy iPS cells. Characterization of the neurons at the single-cell and neuronal network level revealed consistent discriminative properties that distinguished EHMT1-mutant from wildtype neurons. Mutant neuronal networks exhibited network bursting with a reduced rate, longer duration, and increased temporal irregularity compared to control networks. We show that these changes were mediated by the upregulation of the NMDA receptor (NMDAR) subunit 1 and correlate with reduced deposition of the repressive H3K9me2 mark, the catalytic product of EHMT1, at the GRIN1 promoter. Furthermore, we show that EHMT1 deficiency in mice leads to similar neuronal network impairments and increased NMDAR function. Finally, we could rescue the KS patient-derived neuronal network phenotypes by pharmacological inhibition of NMDARs. Together, our results demonstrate a direct link between EHMT1 deficiency in human neurons and NMDAR hyperfunction, providing the basis for a more targeted therapeutic approach to treating KS.
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- 2019
14. Neuronal network dysfunction in a model for Kleefstra syndrome mediated by enhanced NMDAR signaling
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Huiqing Zhou, Tjitske Kleefstra, Teun M. Klein Gunnewiek, Astrid R. Oudakker, Dirk Schubert, Moritz Negwer, Hans van Bokhoven, Ilse M. van der Werf, Katharina Foreman, Monica Frega, Jon-Ruben van Rhijn, Güvem Gümüş-Akay, Katrin Linda, Nael Nadif Kasri, Chantal Schoenmaker, Nine Kompier, Britt Mossink, Jason M. Keller, Willem M.R. van den Akker, and Clinical Neurophysiology
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0301 basic medicine ,Male ,General Physics and Astronomy ,Craniofacial Abnormalities ,Mice ,0302 clinical medicine ,Loss of Function Mutation ,Induced pluripotent stem cell ,lcsh:Science ,Kleefstra Syndrome ,Cerebral Cortex ,Neurons ,Multidisciplinary ,Developmental disorders ,Up-Regulation ,Reconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10] ,Histone methyltransferase ,NMDA receptor ,Female ,Molecular Developmental Biology ,Chromosome Deletion ,Chromosomes, Human, Pair 9 ,Heart Defects, Congenital ,Science ,Induced Pluripotent Stem Cells ,Primary Cell Culture ,Nerve Tissue Proteins ,Biology ,Molecular neuroscience ,Receptors, N-Methyl-D-Aspartate ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,EHMT1 ,All institutes and research themes of the Radboud University Medical Center ,Downregulation and upregulation ,Intellectual Disability ,Biological neural network ,Animals ,Humans ,Receptors, AMPA ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,GRIN1 ,General Chemistry ,Histone-Lysine N-Methyltransferase ,Cellular neuroscience ,Disease Models, Animal ,030104 developmental biology ,nervous system ,biology.protein ,lcsh:Q ,Dizocilpine Maleate ,Neuroscience ,Excitatory Amino Acid Antagonists ,030217 neurology & neurosurgery - Abstract
Kleefstra syndrome (KS) is a neurodevelopmental disorder caused by mutations in the histone methyltransferase EHMT1. To study the impact of decreased EHMT1 function in human cells, we generated excitatory cortical neurons from induced pluripotent stem (iPS) cells derived from KS patients. Neuronal networks of patient-derived cells exhibit network bursting with a reduced rate, longer duration, and increased temporal irregularity compared to control networks. We show that these changes are mediated by upregulation of NMDA receptor (NMDAR) subunit 1 correlating with reduced deposition of the repressive H3K9me2 mark, the catalytic product of EHMT1, at the GRIN1 promoter. In mice EHMT1 deficiency leads to similar neuronal network impairments with increased NMDAR function. Finally, we rescue the KS patient-derived neuronal network phenotypes by pharmacological inhibition of NMDARs. Summarized, we demonstrate a direct link between EHMT1 deficiency and NMDAR hyperfunction in human neurons, providing a potential basis for more targeted therapeutic approaches for KS., Kleefstra syndrome is a neurodevelopmental disorder associated with hapoinsufficiency of the histone methyltransferase EHMT1. Here the authors show using induced pluripotent cells-derived neurons from patients that network dysfunction occurs and is due to dysfunction of the NMDA receptor.
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- 2019
15. Distinct pathogenic genes causing intellectual disability and autism exhibit overlapping effects on neuronal network development
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Bijvank E, Martijn Selten, Huiqing Zhou, Nael Nadif Kasri, B. Mossink, Koerner P, Bokhoven Hv, Jason M. Keller, Tjitske Kleefstra, Katrin Linda, Sophie Jansen, Monica Frega, Jieqiong Qu, Astrid R. Oudakker, Dirk Schubert, and Moerschen R
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musculoskeletal diseases ,EHMT1 ,Neurodevelopmental disorder ,Histone methyltransferase ,medicine ,Autism ,Epigenetics ,Biology ,medicine.disease ,Haploinsufficiency ,Neuroscience ,Loss function ,Kleefstra Syndrome - Abstract
Neuronal gene transcription through epigenetic modifications plays an important role in the etiology of intellectual disability (ID) and autism spectrum disorders (ASD). Haploinsufficiency of the Euchromatin Histone Methyltransferase 1 (EHMT1) gene causes Kleefstra syndrome, a neurodevelopmental disorder with the clinical features of both ID and ASD. Interestingly, patients with loss-of-function mutations in the functionally distinct epigenetic regulators MBD5, MLL3 or SMARCB1 also share the same core features, referred to as the Kleefstra syndrome spectrum (KSS). Currently, little is known about how variants in these different chromatin remodelers lead to the phenotypic convergence in KSS. To decipher the pathophysiology underlying KSS we here directly compared the effect of loss of function of four distinct KSS genes in developing rodent neuronal networks, using a combination of transcriptional analysis, immunocytochemistry, single-cell recordings and micro-electrode arrays. KSS gene-deficient neuronal networks all showed impaired neural network activity, resulting in hyperactive networks with altered network organization. At the single-cell level, we found genotype-specific changes in intrinsic excitability and in excitatory-inhibitory balance, all leading to increased excitability. These findings we could also recapitulate in a mouse model for Kleefstra syndrome. Transcriptional analysis further revealed distinct regulatory mechanisms. Nevertheless, KSS-target genes share similar functions in regulating neuronal excitability and synaptic function, several of which are associated with ID and ASD. Our results show that KSS genes mainly converge at the level of neuronal network development, providing new insights into the pathophysiology of KSS and to other phenotypically congruent disorders involving ID and autism.
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- 2018
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16. Brain-on-a chip technologies for investigating neuronal diseases: Toward precision medicine applications
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Monica Frega, Dirk Schubert, Jason M. Keller, Katrin Linda, Nael Nadif Kasri, and B. Mossink
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0301 basic medicine ,Biology ,medicine.disease ,Phenotype ,Hypotonia ,Synapse ,03 medical and health sciences ,030104 developmental biology ,Intellectual disability ,Biological neural network ,medicine ,medicine.symptom ,Stem cell ,Induced pluripotent stem cell ,Neuroscience ,Kleefstra Syndrome - Abstract
Neurodevelopmental disorders (NDDs) are a collection of heterogeneous syndromes involving disruption of early neurobiological development. While the identification of disease genes has great benefits for diagnostic and prognostic purposes, for the vast majority of these genes there is little knowledge about neurobiological mechanisms that they control at the cellular and network level. Recent studies demonstrate that NDDs are "diseases of the synapse". Synaptic malfunction can severely affect network connectivity and dynamic. Understanding the neural circuit basis of NDDs is therefore imperial for a better understanding of these disorders. Kleefstra syndrome (KS) is a NDD characterized by moderate to severe intellectual disability, childhood hypotonia, and facial dysmorphism associated with genes deficiency. Here, we studied how KS genes-deficiency affects neuronal network maturation using dissociated neuronal cultures (i.e. from rodent or KS patient induced pluripotent stem cells). Using micro-electrode arrays technology we characterized the electrophysiological activity of control and KS genes-deficient neuronal networks. We showed that KS genes-deficient neuronal networks exhibited different pattern of synchronous activity compared to control condition. In particular, KS genes-deficiency induced an inappropriate network organization and irregular pattern of activity, indicating that KS genes are required for proper network formation. The neuronal network phenotype found here, provides for relevant future directions in the elucidation of pathophysiology in KS.
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- 2018
17. Neurons derived from induced pluripotent stem cells on microelectrode arrays: a human model for neurodevelopmental disorders
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Nael Nadif Kasri, Britt Mossink, Monica Frega, Dirk Schubert, Sebastian Van Gestel, Jason M. Keller, Katrin Linda, and Jon-Ruben van Rhijn
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Cellular and Molecular Neuroscience ,Microelectrode ,Chemistry ,Induced pluripotent stem cell ,Cell biology - Published
- 2018
18. Cell-type specific contribution to neuronal network (dys)function in neurodevelopmental disorders
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Sophie Janssen, Britt Mossink, Dirk Schubert, Nael Nadif Kasri, Katrin Linda, Chantal Schoenmaker, Jason M. Keller, Jon-Ruben van Rhijn, and Monica Frega
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Cellular and Molecular Neuroscience ,Cell type specific ,Biological neural network ,Biology ,Neuroscience ,Function (biology) - Published
- 2018
19. The promise of induced pluripotent stem cells for neurodevelopmental disorders
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Katrin Linda, Nael Nadif Kasri, and Carol Fiuza
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0301 basic medicine ,medicine.medical_specialty ,Induced Pluripotent Stem Cells ,Rett syndrome ,03 medical and health sciences ,0302 clinical medicine ,Intellectual disability ,medicine ,Animals ,Humans ,Induced pluripotent stem cell ,Biological Psychiatry ,Pharmacology ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,business.industry ,Cognition ,medicine.disease ,Fragile X syndrome ,030104 developmental biology ,Neurodevelopmental Disorders ,Synapses ,Autism ,Medical genetics ,Synaptopathy ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Item does not contain fulltext A major challenge in clinical genetics and medicine is represented by genetically and phenotypically highly diverse neurodevelopmental disorders, like for example intellectual disability and autism. Intellectual disability is characterized by substantial limitations in cognitive function and adaptive behaviour. At the cellular level, this is reflected by deficits in synaptic structure and plasticity and therefore has been coined as a synaptic disorder or "synaptopathy". In this review, we summarize the findings from recent studies in which iPSCs have been used to model specific neurodevelopmental syndromes, including Fragile X syndrome, Rett syndrome, Williams-Beuren syndrome and Phelan-McDermid syndrome. We discuss what we have learned from these studies and what key issues need to be addressed to move the field forward.
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- 2018
20. Rapid neuronal differentiation of induced pluripotent stem cells for measuring network activity on micro-electrode arrays
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Katrin Linda, Cornelis A. Albers, Nael Nadif Kasri, Monica Frega, Jori van der Raadt, Dirk Schubert, Jason M. Keller, Jon-Ruben van Rhijn, and Sebastianus H C van Gestel
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0301 basic medicine ,induced pluripotent stem cells ,Cellular differentiation ,Neurogenesis ,General Chemical Engineering ,Population ,Genetic Vectors ,Neurophysiology ,Nerve Tissue Proteins ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,03 medical and health sciences ,Biological neural network ,Basic Helix-Loop-Helix Transcription Factors ,Humans ,Issue 119 ,Induced pluripotent stem cell ,education ,neuronal differentiation ,Neurons ,education.field_of_study ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,General Immunology and Microbiology ,General Neuroscience ,Lentivirus ,lentiviral transduction ,Cell Differentiation ,Fibroblasts ,Cellular Reprogramming ,Microarray Analysis ,astrocyte isolation ,Electrophysiology ,030104 developmental biology ,nervous system ,Cell culture ,micro-electrode arrays ,neuronal network ,Molecular Developmental Biology ,Neurodevelopmental disorders Radboud Institute for Molecular Life Sciences [Radboudumc 7] ,Neuroscience ,Developmental biology ,Microelectrodes ,Transcription Factors ,Developmental Biology - Abstract
Contains fulltext : 168902.pdf (Publisher’s version ) (Open Access) Neurons derived from human induced Pluripotent Stem Cells (hiPSCs) provide a promising new tool for studying neurological disorders. In the past decade, many protocols for differentiating hiPSCs into neurons have been developed. However, these protocols are often slow with high variability, low reproducibility, and low efficiency. In addition, the neurons obtained with these protocols are often immature and lack adequate functional activity both at the single-cell and network levels unless the neurons are cultured for several months. Partially due to these limitations, the functional properties of hiPSC-derived neuronal networks are still not well characterized. Here, we adapt a recently published protocol that describes production of human neurons from hiPSCs by forced expression of the transcription factor neurogenin-212. This protocol is rapid (yielding mature neurons within 3 weeks) and efficient, with nearly 100% conversion efficiency of transduced cells (>95% of DAPI-positive cells are MAP2 positive). Furthermore, the protocol yields a homogeneous population of excitatory neurons that would allow the investigation of cell-type specific contributions to neurological disorders. We modified the original protocol by generating stably transduced hiPSC cells, giving us explicit control over the total number of neurons. These cells are then used to generate hiPSC-derived neuronal networks on micro-electrode arrays. In this way, the spontaneous electrophysiological activity of hiPSC-derived neuronal networks can be measured and characterized, while retaining interexperimental consistency in terms of cell density. The presented protocol is broadly applicable, especially for mechanistic and pharmacological studies on human neuronal networks. 10 p.
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- 2017
21. Mouse models of 17q21.31 microdeletion and microduplication syndromes highlight the importance of Kansl1 for cognition
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Giovanni Iacono, Katrin Linda, Claire Chevalier, Nael Nadif Kasri, Hamid Meziane, Yann Humeau, Xander Houbaert, Bert B.A. de Vries, Maksym V. Kopanitsa, Thomas Arbogast, Yann Herault, Marie-Christine Birling, R. Mark Henkelman, David A. Koolen, Henk Stunnenberg, Nurudeen O. Afinowi, Tania Sorg, Matthijs C. van Eede, Mohammed Selloum, and Christine L. Laliberté
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0301 basic medicine ,Male ,Cancer Research ,Physiology ,CNTNAP2 ,Hippocampus ,Social Sciences ,medicine.disease_cause ,Synaptic Transmission ,Epigenesis, Genetic ,Mice ,Cognition ,Sociology ,Gene duplication ,Chromosome Duplication ,Medicine and Health Sciences ,Genetics (clinical) ,Genetics ,Mammals ,Genetics & Heredity ,Gene Rearrangement ,Mice, Knockout ,Mutation ,Neuronal Plasticity ,Animal Behavior ,DEVELOPMENTAL DELAY ,ABNORMALITIES ,Neurogenesis ,Brain ,Nuclear Proteins ,Animal Models ,Social Discrimination ,ASSOCIATION ,ATLAS ,Phenotype ,Up-Regulation ,Experimental Organism Systems ,Chromosome Structures ,Animal Sociality ,Chromosomal region ,Vertebrates ,Female ,Anatomy ,Chromosome Deletion ,CLINICAL SPECTRUM ,Life Sciences & Biomedicine ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,Research Article ,lcsh:QH426-470 ,DNA Copy Number Variations ,Mouse Models ,Biology ,Research and Analysis Methods ,Rodents ,03 medical and health sciences ,Model Organisms ,Intellectual Disability ,medicine ,Animals ,Abnormalities, Multiple ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Behavior ,0604 Genetics ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Science & Technology ,Biological Locomotion ,MUTATIONS ,AUTISM SPECTRUM DISORDER ,Neurotransmission ,Body Weight ,Organisms ,Biology and Life Sciences ,Gene rearrangement ,GENE ,Mice, Inbred C57BL ,lcsh:Genetics ,Disease Models, Animal ,030104 developmental biology ,dup ,Amniotes ,Zoology ,Gene Deletion ,Neuroscience ,Chromosomes, Human, Pair 17 ,Developmental Biology - Abstract
Koolen-de Vries syndrome (KdVS) is a multi-system disorder characterized by intellectual disability, friendly behavior, and congenital malformations. The syndrome is caused either by microdeletions in the 17q21.31 chromosomal region or by variants in the KANSL1 gene. The reciprocal 17q21.31 microduplication syndrome is associated with psychomotor delay, and reduced social interaction. To investigate the pathophysiology of 17q21.31 microdeletion and microduplication syndromes, we generated three mouse models: 1) the deletion (Del/+); or 2) the reciprocal duplication (Dup/+) of the 17q21.31 syntenic region; and 3) a heterozygous Kansl1 (Kans1+/-) model. We found altered weight, general activity, social behaviors, object recognition, and fear conditioning memory associated with craniofacial and brain structural changes observed in both Del/+ and Dup/+ animals. By investigating hippocampus function, we showed synaptic transmission defects in Del/+ and Dup/+ mice. Mutant mice with a heterozygous loss-of-function mutation in Kansl1 displayed similar behavioral and anatomical phenotypes compared to Del/+ mice with the exception of sociability phenotypes. Genes controlling chromatin organization, synaptic transmission and neurogenesis were upregulated in the hippocampus of Del/+ and Kansl1+/- animals. Our results demonstrate the implication of KANSL1 in the manifestation of KdVS phenotypes and extend substantially our knowledge about biological processes affected by these mutations. Clear differences in social behavior and gene expression profiles between Del/+ and Kansl1+/- mice suggested potential roles of other genes affected by the 17q21.31 deletion. Together, these novel mouse models provide new genetic tools valuable for the development of therapeutic approaches., Author summary The 17q21.31 deletion syndrome, also named Koolen-de Vries syndrome (KdVS), is a rare copy number variants associated in humans with intellectual disability, friendly behavior, congenital malformations. The syndrome is caused either by microdeletions in the 17q21.31 region or by variants in the KANSL1 gene in human. The reciprocal 17q21.31 microduplication syndrome is not so well characterized. To investigate the pathophysiology of the syndromes, we studied the deletion, the duplication of the syntenic region and a heterozygous Kansl1 mutant in the mouse. We found affected morphology and cognition, similar to human condition, with genes controlling chromatin organization, synaptic transmission and neurogenesis dysregulated in the hippocampus of KdVS models. In addition we found that synaptic transmission was altered in KdVS mice. Our results demonstrate the implication of KANSL1 in the manifestation of KdVS and extend substantially our knowledge about altered biological processes. Nevertheless, phenotypic differences between deletion and Kansl1+/- models suggested roles of other genes affected by the 17q21.31 deletion.
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- 2017
22. Added effects of dexamethasone and mesenchymal stem cells on early Natural Killer cell activation
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Clive M. Michelo, Arnold van der Meer, Bram van Cranenbroek, Heba Abdelrazik, Esther Fasse, Katrin Linda, and Irma Joosten
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0301 basic medicine ,Antigens, Differentiation, T-Lymphocyte ,Graft Rejection ,medicine.medical_treatment ,immunosuppressive drugs ,Graft vs Host Disease ,NK cells ,Pharmacology ,Lymphocyte Activation ,Dexamethasone ,corticosteroids ,0302 clinical medicine ,Cyclosporin a ,STAT5 Transcription Factor ,Immunology and Allergy ,Interferon gamma ,Phosphorylation ,Cells, Cultured ,biology ,STAT4 Transcription Factor ,Combined Modality Therapy ,Interleukin-12 ,Up-Regulation ,Killer Cells, Natural ,030220 oncology & carcinogenesis ,hematopoietic stem cell transplantation ,Interleukin 12 ,Natural killer cell activation ,Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5] ,Immunosuppressive Agents ,medicine.drug ,Immunology ,chemical and pharmacologic phenomena ,Graft vs Leukemia Effect ,03 medical and health sciences ,Interferon-gamma ,Antigens, CD ,medicine ,Humans ,Lectins, C-Type ,Perforin production ,Transplantation ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Perforin ,Mesenchymal stem cell ,Interleukin-2 Receptor alpha Subunit ,Mesenchymal Stem Cells ,Immunotherapy ,030104 developmental biology ,biology.protein ,Cancer research ,Interleukin-2 - Abstract
Contains fulltext : 167939.pdf (Publisher’s version ) (Open Access) Graft rejection and graft-versus-host disease are leading causes of transplant related mortality despite advancements in immunosuppressive therapy. Mesenchymal stem cells (MSCs) offer a promising addition to immunosuppressive drugs (ISD), while NK-cells are increasingly used as effector cells in graft-versus-leukemia. Combined therapy of ISD, NK-cells and/or MSCs is used in clinical practice. Here, we examined the effects of MSCs and selected ISD (tacrolimus, cyclosporin A, mycophenolic acid, dexamethasone) treatment on early NK-cell activation. We assessed STAT4 and STAT5 phosphorylation triggered by IL-12 and IL-2, respectively. Furthermore, we determined IFNgamma, perforin production and the expression pattern of selected NK-cell receptors. Of all drugs tested, only dexamethasone inhibited NK-cell STAT4 and STAT5 phosphorylation. All ISD, with the exception of MPA, significantly inhibited IFNgamma, and only dexamethasone inhibited upregulation of early activation markers CD69 and CD25 (IL-2 condition only). MSCs inhibited IL-2 induced NK cell STAT5 phosphorylation, IFNgamma production and CD69 upregulation, and IL-12 induced IFNgamma and perforin production. While MSCs mediated inhibition of CD69 expression was cell contact dependent, inhibition of IFNgamma and perforin production, as well as STAT5 phosphorylation was cell-contact independent. Importantly, dexamethasone augmented MSCs mediated inhibition of both IL-12 and IL-2 induced CD69 expression and IFNgamma production, as well as IL-2 induced STAT5 phosphorylation. Taken together, these novel insights may help the design of future NK-cell and MSCs based immunotherapy.
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- 2016
23. Neuronal Networks Coupled To Microelectrode Arrays: Network Maturation Impairments In Neurodevelopmental Disorders
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Monica, Frega, primary, Jason, Keller, additional, Britt, Mossink, additional, Katrin, Linda, additional, Bas, Van Gestel, additional, Nael, Kasri, additional, and Dirk, Schubert, additional
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- 2016
- Full Text
- View/download PDF
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