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. Two of the mutations are nonsense mutations that truncate the C-terminal region of SIK1. 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. We generated SIK1 mutant (SIK1-MT) mice recapitulating the C-terminal truncated mutations using CRISPR/Cas9-mediated genome editing. 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. These results indicate that risperidone have a role to decrease the neuronal excitability and excitatory synapses, ameliorating repetitive behavior in the SIK1 truncated mice.

中文翻译：

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利培酮缓解与ASD相关的SIK1突变引起的兴奋性神经元功能增强和重复行为

在伴有自闭症状的早期婴儿癫痫性脑病（EIEE-30）患者中，已经确定了盐诱导型激酶1（SIK1）编码基因的六个突变。其中两个突变是无义突变，可截断SIK1的C端区域。已经显示SIK1蛋白的C末端截短形式影响SIK1蛋白的亚细胞分布，试图推测与疾病的病理生理学的相关性。我们使用CRISPR / Cas9介导的基因组编辑生成了CIK截短突变的SIK1突变（SIK1-MT）小鼠。SIK1-MT蛋白分布在细胞核和细胞质中，而野生型SIK1的分布仅限于细胞核。我们发现，由于SIK1-MT小鼠内侧前额叶皮层第5层的锥体神经元兴奋性突触传递增加和神经兴奋性增强，导致兴奋性和抑制性（E / I）突触平衡受到破坏。我们还发现SIK1-MT小鼠中重复行为和社交行为缺陷的增加。利培酮给药减弱了神经兴奋性和兴奋性突触传递，但是破坏的E / I突触平衡没有改变，因为它也降低了抑制性突触传递。利培酮还消除了重复行为，但没有消除社会行为缺陷。这些结果表明，利培酮具有降低神经元兴奋性和兴奋性突触的作用，改善了SIK1截短小鼠的重复行为。