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

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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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