Risperidone Mitigates Enhanced Excitatory Neuronal Function and Repetitive Behavior Caused by an ASD-Associated Mutation of SIK1

Six mutations in the salt-inducible kinase 1 (SIK1)-coding gene have been identified patients with early infantile epileptic encephalopathy (EIEE-30) accompanied by autistic symptoms. Two of are non-sense that truncate C-terminal region SIK1. It has shown C-terminal-truncated form SIK1 protein affects subcellular distribution protein, tempting to speculate relevance pathophysiology disorders. We generated SIK1-mutant (SIK1-MT) mice recapitulating using CRISPR/Cas9-mediated genome editing. SIK1-MT was distributed nucleus and cytoplasm, whereas wild-type restricted nucleus. found disruption excitatory inhibitory (E/I) synaptic balance due an increase transmission enhancement neural excitability pyramidal neurons layer 5 medial prefrontal cortex mice. also increased repetitive behavior social behavioral deficits The risperidone administration attenuated transmission, but disrupted E/I unchanged, because it reduced transmission. Risperidone eliminated not deficits. These results indicate a role decreasing neuronal synapses, ameliorating SIK1-truncated