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

Abstract

Six mutations in the salt-inducible kinase 1 (SIK1)-coding gene have been identified in patients with early infantile epileptic encephalopathy (EIEE-30) accompanied by autistic symptoms. Two of the mutations are non-sense 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 has a role in decreasing neuronal excitability and excitatory synapses, ameliorating repetitive behavior in the SIK1-truncated mice.

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

“…Truncations of the SIK1 gene in two patients with infantile spasms occurred within a nuclear localization domain (NLD) in the C-terminal region [ 14 ]. We previously established a mouse line with a frame-shift mutation in the SIK1 gene that produces a truncated form of SIK1 protein and studied heterozygote SIK1-MT mice as models for human patients ( Figure 1 A) [ 15 ]. In this study, we analyzed male heterozygote SIK1-MT mice as models for DEE-30 and, hereafter, referred to them as SIK1-MT mice.…”

“…SIK1 phosphorylates type II HDAC and removes it from MEF2. The C-terminal truncated form of SIK1 is unable to reside in the nucleus, therefore, it cannot activate the MEF2-mediated target gene transcription [ 14 , 15 , 25 , 32 ]. Cytosolic SIK1 phosphorylates CRTC, a coactivator for CREB [ 7 , 30 , 31 ].…”

“…We previously generated SIK1 mutant (SIK1-MT) mice recapitulating the C-terminal truncated mutation of SIK1 using CRISPR/Cas9-mediated genome editing as a disease model of the human cases [ 15 ]. Heterozygote SIK1-MT mice exhibited autistic behaviors, including repetitive behaviors and impaired social interactions, as seen in human patients.…”

Repetitive Restricted Behaviors in Autism Spectrum Disorder: From Mechanism to Development of Therapeutics

“…Risperidone and aripiprazole, the atypical antipsychotic drugs acting on the D2 dopamine receptor, have been approved to reduce irritability, agitation, aggression, and self-harm in ASD by the Food and Drug Administration (FDA) ( McCracken et al, 2002 ; Owen et al, 2009 ). Although risperidone has been reported to reduce RRBs in salt-induced kinase 1 (SIK1)-mutant mice via attenuating neural excitability and excitatory synaptic transmission ( Badawi et al, 2021 ), a meta-analysis published in 2020 showed that antipsychotics were not beneficial to RRBs in clinical trials ( Yu et al, 2020 ). Subsequently, another meta-analysis including more RCTs pointed out a slight improvement in RRBs after administration of antipsychotics ( Zhou et al, 2021 ).…”

IQSEC2 Deficiency Results in Abnormal Social Behaviors Relevant to Autism by Affecting Functions of Neural Circuits in the Medial Prefrontal Cortex

“…Irrespective of the age of mice, patch-clamp recording from acute brain slices was performed as described previously [29,30]. Briefly, postnatal day 14-19 or postnatal day 35-40 the mice were shortly anesthetized with Isoflurane and decapitated.…”