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

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.

Epileptic responses in marmosets induced by knockdown of CREB Regulated Transcription Coactivator 1 (CRTC1)

“…shCRTC1 injection could eventually cause a situation similar to status epilepticus, but it needs to be confirmed.We illustrated a possible pathway that involved in CRTC1 KD induced cell-death signals, followed by aberrant IEG expression (Figure S10). In addition to the Figure S10 legend, de novo SIK1 mutations cause SIK syndrome, impacting HDAC5, synaptic activity response genes in humans and mice 25–27 . SIK1 variation disrupts MEF2 , Nur77 (NR4A1) and Neureglin 1 expressions 25 .…”

“…In addition to the Fig. 8 legend, de novo SIK1 mutations cause SIK syndrome, impacting HDAC5, synaptic activity response genes in humans and mice [28][29][30] . SIK1 variation disrupts MEF2, Nur77 (NR4A1) and Neureglin 1 expressions 28 .…”

“…Either phosphorylated CREB or nonphosphorylated CREB can activate cre dependent IEG expression together with CRTC1 20 , both of which pathways are thought to be reduced by CRTC1 KD. ⑦ A few reports have implicated SIK1 in epilepsy [28][29][30] . SIK1 is a class II HDAC kinase and promotes skeletal myocyte survival 52 .…”

Diverse Clinical Phenotypes of CASK-Related Disorders and Multiple Functional Domains of CASK Protein

“…Various mutations in the gene of GluN2B were found in patients suffering from infantile epilepsy [ 101 , 102 ]. The administration of NMDA has been used as a rodent model of infantile epilepsy [ 103 , 104 , 105 ]. The guanylate kinase domain at the C-terminal of CASK interacts with T-box transcription factor-1 (TBR1) and CASK regulates the gene expression of GluN2B in a TBR1-dependent manner [ 40 , 43 ].…”

Blocking salt‐inducible kinases with YKL‐06‐061 prevents PTZ‐induced seizures in mice

“…Moreover, individuals with SIK1 mutations have shorter survival in cases of neonatal epilepsy onset and autism plus developmental syndrome after infantile spasms in others (Hansen et al., 2015 ). Furthermore, SIK1 mutant mice, recapitulating the C‐terminal‐truncated mutation of SIK1, displayed enhanced seizure susceptibility (Pang et al., 2022 ). Despite recent reports revealing the role of SIKs in the development of epileptic seizures (Proschel et al., 2017 ), the causal link and mechanisms underlying the participation of SIKs in epileptogenesis remain poorly understood.…”