Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns
Abstract Background Fragile X syndrome (FXS), a neurodevelopmental disorder, is a leading monogenetic cause of intellectual disability and autism spectrum disorder. Notwithstanding the extensive studies using rodent and other pre-clinical models of FXS, which have provided detailed mechanistic insig...
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2020-06-01
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Series: | Molecular Autism |
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Online Access: | http://link.springer.com/article/10.1186/s13229-020-00351-4 |
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Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shreya Das Sharma Rakhi Pal Bharath Kumar Reddy Bhuvaneish T. Selvaraj Nisha Raj Krishna Kumar Samaga Durga J. Srinivasan Loren Ornelas Dhruv Sareen Matthew R. Livesey Gary J. Bassell Clive N. Svendsen Peter C. Kind Siddharthan Chandran Sumantra Chattarji David J. A. Wyllie |
spellingShingle |
Shreya Das Sharma Rakhi Pal Bharath Kumar Reddy Bhuvaneish T. Selvaraj Nisha Raj Krishna Kumar Samaga Durga J. Srinivasan Loren Ornelas Dhruv Sareen Matthew R. Livesey Gary J. Bassell Clive N. Svendsen Peter C. Kind Siddharthan Chandran Sumantra Chattarji David J. A. Wyllie Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns Molecular Autism Fragile X syndrome Disease-modelling Electrophysiology Action potential |
author_facet |
Shreya Das Sharma Rakhi Pal Bharath Kumar Reddy Bhuvaneish T. Selvaraj Nisha Raj Krishna Kumar Samaga Durga J. Srinivasan Loren Ornelas Dhruv Sareen Matthew R. Livesey Gary J. Bassell Clive N. Svendsen Peter C. Kind Siddharthan Chandran Sumantra Chattarji David J. A. Wyllie |
author_sort |
Shreya Das Sharma |
title |
Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns |
title_short |
Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns |
title_full |
Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns |
title_fullStr |
Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns |
title_full_unstemmed |
Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns |
title_sort |
cortical neurons derived from human pluripotent stem cells lacking fmrp display altered spontaneous firing patterns |
publisher |
BMC |
series |
Molecular Autism |
issn |
2040-2392 |
publishDate |
2020-06-01 |
description |
Abstract Background Fragile X syndrome (FXS), a neurodevelopmental disorder, is a leading monogenetic cause of intellectual disability and autism spectrum disorder. Notwithstanding the extensive studies using rodent and other pre-clinical models of FXS, which have provided detailed mechanistic insights into the pathophysiology of this disorder, it is only relatively recently that human stem cell-derived neurons have been employed as a model system to further our understanding of the pathophysiological events that may underlie FXS. Our study assesses the physiological properties of human pluripotent stem cell-derived cortical neurons lacking fragile X mental retardation protein (FMRP). Methods Electrophysiological whole-cell voltage- and current-clamp recordings were performed on two control and three FXS patient lines of human cortical neurons derived from induced pluripotent stem cells. In addition, we also describe the properties of an isogenic pair of lines in one of which FMR1 gene expression has been silenced. Results Neurons lacking FMRP displayed bursts of spontaneous action potential firing that were more frequent but shorter in duration compared to those recorded from neurons expressing FMRP. Inhibition of large conductance Ca2+-activated K+ currents and the persistent Na+ current in control neurons phenocopies action potential bursting observed in neurons lacking FMRP, while in neurons lacking FMRP pharmacological potentiation of voltage-dependent Na+ channels phenocopies action potential bursting observed in control neurons. Notwithstanding the changes in spontaneous action potential firing, we did not observe any differences in the intrinsic properties of neurons in any of the lines examined. Moreover, we did not detect any differences in the properties of miniature excitatory postsynaptic currents in any of the lines. Conclusions Pharmacological manipulations can alter the action potential burst profiles in both control and FMRP-null human cortical neurons, making them appear like their genetic counterpart. Our studies indicate that FMRP targets that have been found in rodent models of FXS are also potential targets in a human-based model system, and we suggest potential mechanisms by which activity is altered. |
topic |
Fragile X syndrome Disease-modelling Electrophysiology Action potential |
url |
http://link.springer.com/article/10.1186/s13229-020-00351-4 |
work_keys_str_mv |
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doaj-be1ddd0d597d4f079af05cef176f7f962020-11-25T03:47:04ZengBMCMolecular Autism2040-23922020-06-0111111610.1186/s13229-020-00351-4Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patternsShreya Das Sharma0Rakhi Pal1Bharath Kumar Reddy2Bhuvaneish T. Selvaraj3Nisha Raj4Krishna Kumar Samaga5Durga J. Srinivasan6Loren Ornelas7Dhruv Sareen8Matthew R. Livesey9Gary J. Bassell10Clive N. Svendsen11Peter C. Kind12Siddharthan Chandran13Sumantra Chattarji14David J. A. Wyllie15Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative MedicineCentre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative MedicineCentre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative MedicineCentre for Clinical Brain Sciences, University of EdinburghDepartment of Cell Biology, Emory University School of MedicineCentre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative MedicineCentre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative MedicineThe Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical CenterThe Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical CenterCentre for Discovery Brain Sciences, University of EdinburghDepartment of Cell Biology, Emory University School of MedicineThe Board of Governors Regenerative Medicine Institute and Department of Biomedical Sciences, Cedars-Sinai Medical CenterCentre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative MedicineCentre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative MedicineCentre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative MedicineCentre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative MedicineAbstract Background Fragile X syndrome (FXS), a neurodevelopmental disorder, is a leading monogenetic cause of intellectual disability and autism spectrum disorder. Notwithstanding the extensive studies using rodent and other pre-clinical models of FXS, which have provided detailed mechanistic insights into the pathophysiology of this disorder, it is only relatively recently that human stem cell-derived neurons have been employed as a model system to further our understanding of the pathophysiological events that may underlie FXS. Our study assesses the physiological properties of human pluripotent stem cell-derived cortical neurons lacking fragile X mental retardation protein (FMRP). Methods Electrophysiological whole-cell voltage- and current-clamp recordings were performed on two control and three FXS patient lines of human cortical neurons derived from induced pluripotent stem cells. In addition, we also describe the properties of an isogenic pair of lines in one of which FMR1 gene expression has been silenced. Results Neurons lacking FMRP displayed bursts of spontaneous action potential firing that were more frequent but shorter in duration compared to those recorded from neurons expressing FMRP. Inhibition of large conductance Ca2+-activated K+ currents and the persistent Na+ current in control neurons phenocopies action potential bursting observed in neurons lacking FMRP, while in neurons lacking FMRP pharmacological potentiation of voltage-dependent Na+ channels phenocopies action potential bursting observed in control neurons. Notwithstanding the changes in spontaneous action potential firing, we did not observe any differences in the intrinsic properties of neurons in any of the lines examined. Moreover, we did not detect any differences in the properties of miniature excitatory postsynaptic currents in any of the lines. Conclusions Pharmacological manipulations can alter the action potential burst profiles in both control and FMRP-null human cortical neurons, making them appear like their genetic counterpart. Our studies indicate that FMRP targets that have been found in rodent models of FXS are also potential targets in a human-based model system, and we suggest potential mechanisms by which activity is altered.http://link.springer.com/article/10.1186/s13229-020-00351-4Fragile X syndromeDisease-modellingElectrophysiologyAction potential |