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

Pang, Bo and Mori, Takuma and Badawi, Moataz and Zhou, Mengyun and Guo, Qi and Suzuki-Kouyama, Emi and Yanagawa, Toru and Shirai, Yoshinori and Tabuchi, Katsuhiko (2022) 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, 23 (14). 7927. ISSN 1422-0067 (https://doi.org/10.3390/ijms23147927)

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Abstract

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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