An autism-associated mutation in salt inducible kinase 1 causes repetitive behavior and social deficits due to enhanced excitatory neuronal functions in mice.

Abstract Background:Six mutations in the salt inducible kinase 1 (SIK1) coding gene have been identified in the early infantile epileptic encephalopathy (EIEE-30) patients accompanied by autistic symptoms, such as repetitive behavior and social behavioral deficits. Among these mutations, two are nonsense mutations that truncate the C-terminal region. It has been shown that the C-terminal truncated form of SIK1 protein affects the subcellular distribution of SIK1 protein, tempting to speculate the relevance to the pathophysiology of the disorders.Methods:We generated SIK1 mutant (SIK1-MT) mice recapitulating the C-terminal truncated mutations using CRISPR/Cas9-mediated genome editing. We performed cellular assays to examine the subcellular localization of SIK1-MT. We also performed patch clamp electrophysiological recording and behavioral tests to evaluate the neuronal functions and behaviors in SIK1-MT mice. Pharmacological experiments using risperidone were also performed to examine the potential therapeutics of the disorder.Results:SIK1-MT protein was distributed in the nucleus and cytoplasm, whereas the distribution of wild-type SIK1 was restricted to the nucleus. We found the disruption of excitatory and inhibitory (E/I) synaptic balance due to an increase in excitatory synaptic transmission and enhancement of neural excitability in the pyramidal neurons in layer 5 of the medial prefrontal cortex in SIK1-MT mice. We also found the increased repetitive behavior and social behavioral deficits in SIK1-MT mice. The risperidone administration attenuated the neural excitability and excitatory synaptic transmission, but the disrupted E/I synaptic balance was unchanged because it also reduced the inhibitory synaptic transmission. Risperidone also eliminated the repetitive behavior, but not social behavioral deficits.Limitations:We failed to identify drugs that can cure the social behavioral deficits in this mouse model.Conclusions:In the present study, we generated model mice for EIEE-30 recapitulating C-terminal truncated SIK1 mutation discovered in human patients. We found that the C-terminal deletion of SIK1 affects the subcellular distribution of SIK1, resulting in the elevated excitability of neuronal networks and autistic behaviors in the mutant mice. Repetitive behavior, but not social deficits, was restored by risperidone, probably due to the decrease of both excitatory and inhibitory synaptic functions by the drug.