Studies on the autistic-like behavior induced by VRK3 deletion and treatment effects by TrkB stimulation

Abstract

Vaccinia-related kinases (VRKs) are multifaceted serine/threonine kinases that play essential roles in various aspects of cell signaling, cell cycle progression, apoptosis, and neuronal development and differentiation. However, the neuronal function of VRK3 is still unknown in spite of its etiological potential in human autism spectrum disorder (ASD). Here, we report that VRK3-deficient mice exhibited typical symptoms of autism-like behavior including hyperactivity, stereotyped behaviors, reduced social interaction, and impaired context-dependent spatial memory as well as deficits in pain sensation. Significant decrease in dendritic spine number and arborization were identified in the hippocampus CA1 of VRK3-deficient mice. These mice also exhibited a reduced rectification of AMPA receptor-mediated current and changes in expression of synaptic and signaling proteins including TrkB, Arc and CaMKIIα. Notably, TrkB stimulation with 7, 8-dihydroxyflavone (7, 8-DHF) reversed the altered synaptic structure and function, and successfully restored autism-like behavior in VRK3-deficient mice. In addition, we found that peripheral VRK3 plays an important role in pain sensitivity after inflammation and nerve injury. These results reveal that VRK3 plays a critical role in neurodevelopmental disorders and suggest a potential therapeutic strategy for ASD.