An Epilepsy-Associated Mutation of Salt-Inducible Kinase 1 Increases the Susceptibility to Epileptic Seizures and Interferes with Adrenocorticotropic Hormone Therapy for Infantile Spasms in Mice
Six mutations in the salt-inducible kinase 1 (SIK1) have been identified in developmental and epileptic encephalopathy (DEE-30) patients, and two of the mutations are nonsense mutations that truncate the C-terminal region of SIK1. In a previous study, we generated SIK1 mutant (SIK1-MT) mice recapitu...
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2022-07-01
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| author | Bo Pang Takuma Mori Moataz Badawi Mengyun Zhou Qi Guo Emi Suzuki-Kouyama Toru Yanagawa Yoshinori Shirai Katsuhiko Tabuchi |
| author_facet | Bo Pang Takuma Mori Moataz Badawi Mengyun Zhou Qi Guo Emi Suzuki-Kouyama Toru Yanagawa Yoshinori Shirai Katsuhiko Tabuchi |
| author_sort | Bo Pang |
| collection | DOAJ |
| description | Six mutations in the salt-inducible kinase 1 (SIK1) have been identified in developmental and epileptic encephalopathy (DEE-30) patients, and two of the mutations are nonsense mutations that truncate the C-terminal region of SIK1. In a previous study, we generated SIK1 mutant (SIK1-MT) mice recapitulating the C-terminal truncated mutations using CRISPR/Cas9-mediated genome editing and found an increase in excitatory synaptic transmission and enhancement of neural excitability in neocortical neurons in SIK1-MT mice. NMDA was injected into SIK1-MT males to induce epileptic seizures in the mice. The severity of the NMDA-induced seizures was estimated by the latency and the number of tail flickering and hyperflexion. Activated brain regions were evaluated by immunohistochemistry against c-fos, Iba1, and GFAP. As another epilepsy model, pentylenetetrazol was injected into the adult SIK1 mutant mice. Seizure susceptibility induced by both NMDA and PTZ was enhanced in SIK1-MT mice. Brain regions including the thalamus and hypothalamus were strongly activated in NMDA-induced seizures. The epilepsy-associated mutation of SIK1 canceled the pharmacological effects of the ACTH treatment on NMDA-induced seizures. These results suggest that SIK1 may be involved in the neuropathological mechanisms of NMDA-induced spasms and the pharmacological mechanism of ACTH treatment. |
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| spelling | doaj.art-c98c37b5dfd94221bfe09a3eb6cdca0f2023-12-03T15:10:21ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-07-012314792710.3390/ijms23147927An Epilepsy-Associated Mutation of Salt-Inducible Kinase 1 Increases the Susceptibility to Epileptic Seizures and Interferes with Adrenocorticotropic Hormone Therapy for Infantile Spasms in MiceBo Pang0Takuma Mori1Moataz Badawi2Mengyun Zhou3Qi Guo4Emi Suzuki-Kouyama5Toru Yanagawa6Yoshinori Shirai7Katsuhiko Tabuchi8Department of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, JapanDepartment of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, JapanStrathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UKDepartment of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, JapanDepartment of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, JapanDepartment of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, JapanDepartment of Oral and Maxillofacial Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Ibaraki, JapanDepartment of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, JapanDepartment of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, JapanSix mutations in the salt-inducible kinase 1 (SIK1) have been identified in developmental and epileptic encephalopathy (DEE-30) patients, and two of the mutations are nonsense mutations that truncate the C-terminal region of SIK1. In a previous study, we generated SIK1 mutant (SIK1-MT) mice recapitulating the C-terminal truncated mutations using CRISPR/Cas9-mediated genome editing and found an increase in excitatory synaptic transmission and enhancement of neural excitability in neocortical neurons in SIK1-MT mice. NMDA was injected into SIK1-MT males to induce epileptic seizures in the mice. The severity of the NMDA-induced seizures was estimated by the latency and the number of tail flickering and hyperflexion. Activated brain regions were evaluated by immunohistochemistry against c-fos, Iba1, and GFAP. As another epilepsy model, pentylenetetrazol was injected into the adult SIK1 mutant mice. Seizure susceptibility induced by both NMDA and PTZ was enhanced in SIK1-MT mice. Brain regions including the thalamus and hypothalamus were strongly activated in NMDA-induced seizures. The epilepsy-associated mutation of SIK1 canceled the pharmacological effects of the ACTH treatment on NMDA-induced seizures. These results suggest that SIK1 may be involved in the neuropathological mechanisms of NMDA-induced spasms and the pharmacological mechanism of ACTH treatment.https://www.mdpi.com/1422-0067/23/14/7927SIK1DEE-30infantile spasmsACTHNMDA |
| spellingShingle | Bo Pang Takuma Mori Moataz Badawi Mengyun Zhou Qi Guo Emi Suzuki-Kouyama Toru Yanagawa Yoshinori Shirai Katsuhiko Tabuchi An Epilepsy-Associated Mutation of Salt-Inducible Kinase 1 Increases the Susceptibility to Epileptic Seizures and Interferes with Adrenocorticotropic Hormone Therapy for Infantile Spasms in Mice International Journal of Molecular Sciences SIK1 DEE-30 infantile spasms ACTH NMDA |
| title | An Epilepsy-Associated Mutation of Salt-Inducible Kinase 1 Increases the Susceptibility to Epileptic Seizures and Interferes with Adrenocorticotropic Hormone Therapy for Infantile Spasms in Mice |
| title_full | An Epilepsy-Associated Mutation of Salt-Inducible Kinase 1 Increases the Susceptibility to Epileptic Seizures and Interferes with Adrenocorticotropic Hormone Therapy for Infantile Spasms in Mice |
| title_fullStr | An Epilepsy-Associated Mutation of Salt-Inducible Kinase 1 Increases the Susceptibility to Epileptic Seizures and Interferes with Adrenocorticotropic Hormone Therapy for Infantile Spasms in Mice |
| title_full_unstemmed | An Epilepsy-Associated Mutation of Salt-Inducible Kinase 1 Increases the Susceptibility to Epileptic Seizures and Interferes with Adrenocorticotropic Hormone Therapy for Infantile Spasms in Mice |
| title_short | An Epilepsy-Associated Mutation of Salt-Inducible Kinase 1 Increases the Susceptibility to Epileptic Seizures and Interferes with Adrenocorticotropic Hormone Therapy for Infantile Spasms in Mice |
| title_sort | epilepsy associated mutation of salt inducible kinase 1 increases the susceptibility to epileptic seizures and interferes with adrenocorticotropic hormone therapy for infantile spasms in mice |
| topic | SIK1 DEE-30 infantile spasms ACTH NMDA |
| url | https://www.mdpi.com/1422-0067/23/14/7927 |
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