Loss of Grin2a causes a transient delay in the electrophysiological maturation of hippocampal parvalbumin interneurons
Abstract N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ionotropic glutamate receptors that mediate a calcium-permeable component to fast excitatory neurotransmission. NMDARs are heterotetrameric assemblies of two obligate GluN1 subunits (GRIN1) and two GluN2 subunits (GRIN2A-GRIN2D). Sequ...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-05298-9 |
| _version_ | 1827709057419444224 |
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| author | Chad R. Camp Anna Vlachos Chiara Klöckner Ilona Krey Tue G. Banke Nima Shariatzadeh Sarah M. Ruggiero Peter Galer Kristen L. Park Adam Caccavano Sarah Kimmel Xiaoqing Yuan Hongjie Yuan Ingo Helbig Tim A. Benke Johannes R. Lemke Kenneth A. Pelkey Chris J. McBain Stephen F. Traynelis |
| author_facet | Chad R. Camp Anna Vlachos Chiara Klöckner Ilona Krey Tue G. Banke Nima Shariatzadeh Sarah M. Ruggiero Peter Galer Kristen L. Park Adam Caccavano Sarah Kimmel Xiaoqing Yuan Hongjie Yuan Ingo Helbig Tim A. Benke Johannes R. Lemke Kenneth A. Pelkey Chris J. McBain Stephen F. Traynelis |
| author_sort | Chad R. Camp |
| collection | DOAJ |
| description | Abstract N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ionotropic glutamate receptors that mediate a calcium-permeable component to fast excitatory neurotransmission. NMDARs are heterotetrameric assemblies of two obligate GluN1 subunits (GRIN1) and two GluN2 subunits (GRIN2A-GRIN2D). Sequencing data shows that 43% (297/679) of all currently known NMDAR disease-associated genetic variants are within the GRIN2A gene, which encodes the GluN2A subunit. Here, we show that unlike missense GRIN2A variants, individuals affected with disease-associated null GRIN2A variants demonstrate a transient period of seizure susceptibility that begins during infancy and diminishes near adolescence. We show increased circuit excitability and CA1 pyramidal cell output in juvenile mice of both Grin2a +/− and Grin2a −/− mice. These alterations in somatic spiking are not due to global upregulation of most Grin genes (including Grin2b). Deeper evaluation of the developing CA1 circuit led us to uncover age- and Grin2a gene dosing-dependent transient delays in the electrophysiological maturation programs of parvalbumin (PV) interneurons. We report that Grin2a +/+ mice reach PV cell electrophysiological maturation between the neonatal and juvenile neurodevelopmental timepoints, with Grin2a +/− mice not reaching PV cell electrophysiological maturation until preadolescence, and Grin2a −/− mice not reaching PV cell electrophysiological maturation until adulthood. Overall, these data may represent a molecular mechanism describing the transient nature of seizure susceptibility in disease-associated null GRIN2A patients. |
| first_indexed | 2024-03-10T17:14:33Z |
| format | Article |
| id | doaj.art-cf7691bd122c40aa8eaf85252a89fb91 |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-10T17:14:33Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-cf7691bd122c40aa8eaf85252a89fb912023-11-20T10:33:32ZengNature PortfolioCommunications Biology2399-36422023-09-016111610.1038/s42003-023-05298-9Loss of Grin2a causes a transient delay in the electrophysiological maturation of hippocampal parvalbumin interneuronsChad R. Camp0Anna Vlachos1Chiara Klöckner2Ilona Krey3Tue G. Banke4Nima Shariatzadeh5Sarah M. Ruggiero6Peter Galer7Kristen L. Park8Adam Caccavano9Sarah Kimmel10Xiaoqing Yuan11Hongjie Yuan12Ingo Helbig13Tim A. Benke14Johannes R. Lemke15Kenneth A. Pelkey16Chris J. McBain17Stephen F. Traynelis18Department of Pharmacology and Chemical Biology, Emory University School of MedicineSection on Cellular and Synaptic Physiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of HealthInstitute of Human Genetics, University of Leipzig Medical CenterInstitute of Human Genetics, University of Leipzig Medical CenterDepartment of Pharmacology and Chemical Biology, Emory University School of MedicineDepartment of Pharmacology and Chemical Biology, Emory University School of MedicineDivision of Neurology, Children’s Hospital of PhiladelphiaDepartment of Biomedical and Health Informatics, Children’s Hospital of PhiladelphiaUniversity of Colorado School of Medicine and Children’s Hospital ColoradoSection on Cellular and Synaptic Physiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of HealthSection on Cellular and Synaptic Physiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of HealthSection on Cellular and Synaptic Physiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of HealthDepartment of Pharmacology and Chemical Biology, Emory University School of MedicineDivision of Neurology, Children’s Hospital of PhiladelphiaUniversity of Colorado School of Medicine and Children’s Hospital ColoradoInstitute of Human Genetics, University of Leipzig Medical CenterSection on Cellular and Synaptic Physiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of HealthSection on Cellular and Synaptic Physiology, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of HealthDepartment of Pharmacology and Chemical Biology, Emory University School of MedicineAbstract N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ionotropic glutamate receptors that mediate a calcium-permeable component to fast excitatory neurotransmission. NMDARs are heterotetrameric assemblies of two obligate GluN1 subunits (GRIN1) and two GluN2 subunits (GRIN2A-GRIN2D). Sequencing data shows that 43% (297/679) of all currently known NMDAR disease-associated genetic variants are within the GRIN2A gene, which encodes the GluN2A subunit. Here, we show that unlike missense GRIN2A variants, individuals affected with disease-associated null GRIN2A variants demonstrate a transient period of seizure susceptibility that begins during infancy and diminishes near adolescence. We show increased circuit excitability and CA1 pyramidal cell output in juvenile mice of both Grin2a +/− and Grin2a −/− mice. These alterations in somatic spiking are not due to global upregulation of most Grin genes (including Grin2b). Deeper evaluation of the developing CA1 circuit led us to uncover age- and Grin2a gene dosing-dependent transient delays in the electrophysiological maturation programs of parvalbumin (PV) interneurons. We report that Grin2a +/+ mice reach PV cell electrophysiological maturation between the neonatal and juvenile neurodevelopmental timepoints, with Grin2a +/− mice not reaching PV cell electrophysiological maturation until preadolescence, and Grin2a −/− mice not reaching PV cell electrophysiological maturation until adulthood. Overall, these data may represent a molecular mechanism describing the transient nature of seizure susceptibility in disease-associated null GRIN2A patients.https://doi.org/10.1038/s42003-023-05298-9 |
| spellingShingle | Chad R. Camp Anna Vlachos Chiara Klöckner Ilona Krey Tue G. Banke Nima Shariatzadeh Sarah M. Ruggiero Peter Galer Kristen L. Park Adam Caccavano Sarah Kimmel Xiaoqing Yuan Hongjie Yuan Ingo Helbig Tim A. Benke Johannes R. Lemke Kenneth A. Pelkey Chris J. McBain Stephen F. Traynelis Loss of Grin2a causes a transient delay in the electrophysiological maturation of hippocampal parvalbumin interneurons Communications Biology |
| title | Loss of Grin2a causes a transient delay in the electrophysiological maturation of hippocampal parvalbumin interneurons |
| title_full | Loss of Grin2a causes a transient delay in the electrophysiological maturation of hippocampal parvalbumin interneurons |
| title_fullStr | Loss of Grin2a causes a transient delay in the electrophysiological maturation of hippocampal parvalbumin interneurons |
| title_full_unstemmed | Loss of Grin2a causes a transient delay in the electrophysiological maturation of hippocampal parvalbumin interneurons |
| title_short | Loss of Grin2a causes a transient delay in the electrophysiological maturation of hippocampal parvalbumin interneurons |
| title_sort | loss of grin2a causes a transient delay in the electrophysiological maturation of hippocampal parvalbumin interneurons |
| url | https://doi.org/10.1038/s42003-023-05298-9 |
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