Adult-born neurons in critical period maintain hippocampal seizures via local aberrant excitatory circuits
Abstract Temporal lobe epilepsy (TLE), one common type of medically refractory epilepsy, is accompanied with altered adult-born dentate granule cells (abDGCs). However, the causal role of abDGCs in recurrent seizures of TLE is not fully understood. Here, taking advantage of optogenetic and chemogene...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-06-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-023-01433-4 |
| _version_ | 1827928425355018240 |
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| author | Liying Chen Yingwei Xu Heming Cheng Zhongxia Li Nanxi Lai Menghan Li Yeping Ruan Yang Zheng Fan Fei Cenglin Xu Jiao Ma Shuang Wang Yan Gu Feng Han Zhong Chen Yi Wang |
| author_facet | Liying Chen Yingwei Xu Heming Cheng Zhongxia Li Nanxi Lai Menghan Li Yeping Ruan Yang Zheng Fan Fei Cenglin Xu Jiao Ma Shuang Wang Yan Gu Feng Han Zhong Chen Yi Wang |
| author_sort | Liying Chen |
| collection | DOAJ |
| description | Abstract Temporal lobe epilepsy (TLE), one common type of medically refractory epilepsy, is accompanied with altered adult-born dentate granule cells (abDGCs). However, the causal role of abDGCs in recurrent seizures of TLE is not fully understood. Here, taking advantage of optogenetic and chemogenetic tools to selectively manipulate abDGCs in a reversible manner, combined with Ca2+ fiber photometry, trans-synaptic viral tracing, in vivo/vitro electrophysiology approaches, we aimed to test the role of abDGCs born at different period of epileptogenic insult in later recurrent seizures in mouse TLE models. We found that abDGCs were functionally inhibited during recurrent seizures. Optogenetic activation of abDGCs significantly extended, while inhibition curtailed, the seizure duration. This seizure-modulating effect was attributed to specific abDGCs born at a critical early phase after kindled status, which experienced specific type of circuit re-organization. Further, abDGCs extended seizure duration via local excitatory circuit with early-born granule cells (ebDGCs). Repeated modulation of “abDGC-ebDGC” circuit may easily induce a change of synaptic plasticity, and achieve long-term anti-seizure effects in both kindling and kainic acid-induced TLE models. Together, we demonstrate that abDGCs born at a critical period of epileptogenic insult maintain seizure duration via local aberrant excitatory circuits, and inactivation of these aberrant circuits can long-termly alleviate severity of seizures. This provides a deeper and more comprehensive understanding of the potential pathological changes of abDGCs circuit and may be helpful for the precise treatment in TLE. |
| first_indexed | 2024-03-13T06:08:31Z |
| format | Article |
| id | doaj.art-7a4f5a41d79a461097d368005b81d20b |
| institution | Directory Open Access Journal |
| issn | 2059-3635 |
| language | English |
| last_indexed | 2024-03-13T06:08:31Z |
| publishDate | 2023-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj.art-7a4f5a41d79a461097d368005b81d20b2023-06-11T11:26:34ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352023-06-018111610.1038/s41392-023-01433-4Adult-born neurons in critical period maintain hippocampal seizures via local aberrant excitatory circuitsLiying Chen0Yingwei Xu1Heming Cheng2Zhongxia Li3Nanxi Lai4Menghan Li5Yeping Ruan6Yang Zheng7Fan Fei8Cenglin Xu9Jiao Ma10Shuang Wang11Yan Gu12Feng Han13Zhong Chen14Yi Wang15Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, School of Medicine, Zhejiang UniversityInstitute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, School of Medicine, Zhejiang UniversityKey Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical UniversityKey Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical UniversityInstitute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, School of Medicine, Zhejiang UniversityKey Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical UniversityKey Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical UniversityKey Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical UniversityInstitute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, School of Medicine, Zhejiang UniversityKey Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical UniversityInstitute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, School of Medicine, Zhejiang UniversityInstitute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, School of Medicine, Zhejiang UniversityInstitute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, School of Medicine, Zhejiang UniversityKey Laboratory of Cardiovascular & Cerebrovascular Medicine, Drug Target and Drug Discovery Center, School of Pharmacy, Nanjing Medical UniversityInstitute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, School of Medicine, Zhejiang UniversityInstitute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, School of Medicine, Zhejiang UniversityAbstract Temporal lobe epilepsy (TLE), one common type of medically refractory epilepsy, is accompanied with altered adult-born dentate granule cells (abDGCs). However, the causal role of abDGCs in recurrent seizures of TLE is not fully understood. Here, taking advantage of optogenetic and chemogenetic tools to selectively manipulate abDGCs in a reversible manner, combined with Ca2+ fiber photometry, trans-synaptic viral tracing, in vivo/vitro electrophysiology approaches, we aimed to test the role of abDGCs born at different period of epileptogenic insult in later recurrent seizures in mouse TLE models. We found that abDGCs were functionally inhibited during recurrent seizures. Optogenetic activation of abDGCs significantly extended, while inhibition curtailed, the seizure duration. This seizure-modulating effect was attributed to specific abDGCs born at a critical early phase after kindled status, which experienced specific type of circuit re-organization. Further, abDGCs extended seizure duration via local excitatory circuit with early-born granule cells (ebDGCs). Repeated modulation of “abDGC-ebDGC” circuit may easily induce a change of synaptic plasticity, and achieve long-term anti-seizure effects in both kindling and kainic acid-induced TLE models. Together, we demonstrate that abDGCs born at a critical period of epileptogenic insult maintain seizure duration via local aberrant excitatory circuits, and inactivation of these aberrant circuits can long-termly alleviate severity of seizures. This provides a deeper and more comprehensive understanding of the potential pathological changes of abDGCs circuit and may be helpful for the precise treatment in TLE.https://doi.org/10.1038/s41392-023-01433-4 |
| spellingShingle | Liying Chen Yingwei Xu Heming Cheng Zhongxia Li Nanxi Lai Menghan Li Yeping Ruan Yang Zheng Fan Fei Cenglin Xu Jiao Ma Shuang Wang Yan Gu Feng Han Zhong Chen Yi Wang Adult-born neurons in critical period maintain hippocampal seizures via local aberrant excitatory circuits Signal Transduction and Targeted Therapy |
| title | Adult-born neurons in critical period maintain hippocampal seizures via local aberrant excitatory circuits |
| title_full | Adult-born neurons in critical period maintain hippocampal seizures via local aberrant excitatory circuits |
| title_fullStr | Adult-born neurons in critical period maintain hippocampal seizures via local aberrant excitatory circuits |
| title_full_unstemmed | Adult-born neurons in critical period maintain hippocampal seizures via local aberrant excitatory circuits |
| title_short | Adult-born neurons in critical period maintain hippocampal seizures via local aberrant excitatory circuits |
| title_sort | adult born neurons in critical period maintain hippocampal seizures via local aberrant excitatory circuits |
| url | https://doi.org/10.1038/s41392-023-01433-4 |
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