Mosaic and non-mosaic protocadherin 19 mutation leads to neuronal hyperexcitability in zebrafish
Epilepsy is one of the most common neurological disorders. The X-linked gene PCDH19 is associated with sporadic and familial epilepsy in humans, typically with early-onset clustering seizures and intellectual disability in females but not in so-called ‘carrier’ males, suggesting that mosaic PCDH19 e...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-07-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996122001309 |
| _version_ | 1818211461182259200 |
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| author | Barbara K. Robens Xinzhu Yang Christopher M. McGraw Laura H. Turner Carsten Robens Summer Thyme Alexander Rotenberg Annapurna Poduri |
| author_facet | Barbara K. Robens Xinzhu Yang Christopher M. McGraw Laura H. Turner Carsten Robens Summer Thyme Alexander Rotenberg Annapurna Poduri |
| author_sort | Barbara K. Robens |
| collection | DOAJ |
| description | Epilepsy is one of the most common neurological disorders. The X-linked gene PCDH19 is associated with sporadic and familial epilepsy in humans, typically with early-onset clustering seizures and intellectual disability in females but not in so-called ‘carrier’ males, suggesting that mosaic PCDH19 expression is required to produce epilepsy. To characterize the role of loss of PCDH19 function in epilepsy, we generated zebrafish with truncating pcdh19 variants. Evaluating zebrafish larvae for electrophysiological abnormalities, we observed hyperexcitability phenotypes in both mosaic and non-mosaic pcdh19+/− and pcdh19−/− mutant larvae. Thus, we demonstrate that the key feature of epilepsy—network hyperexcitability—can be modeled effectively in zebrafish, even though overt spontaneous seizure-like swim patterns were not observed. Further, zebrafish with non-mosaic pcdh19 mutation displayed reduced numbers of inhibitory interneurons suggesting a potential cellular basis for the observed hyperexcitability. Our findings in both mosaic and non-mosaic pcdh19 mutant zebrafish challenge the prevailing theory that mosaicism governs all PCDH19-related phenotypes and point to interneuron-mediated mechanisms underlying these phenotypes. |
| first_indexed | 2024-12-12T05:32:52Z |
| format | Article |
| id | doaj.art-9d1b7d0165544333ad1a0010a15bfcb8 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-12T05:32:52Z |
| publishDate | 2022-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-9d1b7d0165544333ad1a0010a15bfcb82022-12-22T00:36:16ZengElsevierNeurobiology of Disease1095-953X2022-07-01169105738Mosaic and non-mosaic protocadherin 19 mutation leads to neuronal hyperexcitability in zebrafishBarbara K. Robens0Xinzhu Yang1Christopher M. McGraw2Laura H. Turner3Carsten Robens4Summer Thyme5Alexander Rotenberg6Annapurna Poduri7Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital – Harvard Medical School, Boston, MA, USA; Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital – Harvard Medical School, Boston, MA, USA.Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital – Harvard Medical School, Boston, MA, USA; Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital – Harvard Medical School, Boston, MA, USA.Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital – Harvard Medical School, Boston, MA, USA; Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital – Harvard Medical School, Boston, MA, USA.; Department of Neurology, Harvard Medical School, Boston, MA, USA; Division of Epilepsy, Department of Neurology, Massachusetts General Hospital, Boston, MA, USADepartment of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital – Harvard Medical School, Boston, MA, USA; Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital – Harvard Medical School, Boston, MA, USA.MIT-Harvard Center for Ultracold Atoms, Research Laboratory of Electronics, and Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USADepartment of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USADepartment of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital – Harvard Medical School, Boston, MA, USA; Department of Neurology, Harvard Medical School, Boston, MA, USA; Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA, USADepartment of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital – Harvard Medical School, Boston, MA, USA; Epilepsy Genetics Program, Department of Neurology, Boston Children's Hospital – Harvard Medical School, Boston, MA, USA.; Department of Neurology, Harvard Medical School, Boston, MA, USA; Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital, Boston, MA, USA; Corresponding author at: Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital – Harvard Medical School, Boston, MA, USA.Epilepsy is one of the most common neurological disorders. The X-linked gene PCDH19 is associated with sporadic and familial epilepsy in humans, typically with early-onset clustering seizures and intellectual disability in females but not in so-called ‘carrier’ males, suggesting that mosaic PCDH19 expression is required to produce epilepsy. To characterize the role of loss of PCDH19 function in epilepsy, we generated zebrafish with truncating pcdh19 variants. Evaluating zebrafish larvae for electrophysiological abnormalities, we observed hyperexcitability phenotypes in both mosaic and non-mosaic pcdh19+/− and pcdh19−/− mutant larvae. Thus, we demonstrate that the key feature of epilepsy—network hyperexcitability—can be modeled effectively in zebrafish, even though overt spontaneous seizure-like swim patterns were not observed. Further, zebrafish with non-mosaic pcdh19 mutation displayed reduced numbers of inhibitory interneurons suggesting a potential cellular basis for the observed hyperexcitability. Our findings in both mosaic and non-mosaic pcdh19 mutant zebrafish challenge the prevailing theory that mosaicism governs all PCDH19-related phenotypes and point to interneuron-mediated mechanisms underlying these phenotypes.http://www.sciencedirect.com/science/article/pii/S0969996122001309PCDH19Girls clustering epilepsyHyperexcitabilityZebrafishMosaicismEpilepsy |
| spellingShingle | Barbara K. Robens Xinzhu Yang Christopher M. McGraw Laura H. Turner Carsten Robens Summer Thyme Alexander Rotenberg Annapurna Poduri Mosaic and non-mosaic protocadherin 19 mutation leads to neuronal hyperexcitability in zebrafish Neurobiology of Disease PCDH19 Girls clustering epilepsy Hyperexcitability Zebrafish Mosaicism Epilepsy |
| title | Mosaic and non-mosaic protocadherin 19 mutation leads to neuronal hyperexcitability in zebrafish |
| title_full | Mosaic and non-mosaic protocadherin 19 mutation leads to neuronal hyperexcitability in zebrafish |
| title_fullStr | Mosaic and non-mosaic protocadherin 19 mutation leads to neuronal hyperexcitability in zebrafish |
| title_full_unstemmed | Mosaic and non-mosaic protocadherin 19 mutation leads to neuronal hyperexcitability in zebrafish |
| title_short | Mosaic and non-mosaic protocadherin 19 mutation leads to neuronal hyperexcitability in zebrafish |
| title_sort | mosaic and non mosaic protocadherin 19 mutation leads to neuronal hyperexcitability in zebrafish |
| topic | PCDH19 Girls clustering epilepsy Hyperexcitability Zebrafish Mosaicism Epilepsy |
| url | http://www.sciencedirect.com/science/article/pii/S0969996122001309 |
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