Excessive repetitive behavior, enhanced spatial learning, altered dendritic features, and aberrant protein expression in Fbxo25 knockout mice (21905)
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by social communication impairments, restricted interests, and repetitive behaviors. A microdeletion in the 8p23.2-pter region has been identified in a Taiwanese ASD boy. The gene encodes F-box only protein 25 (FBXO25), a component of SCF (Skp1-Cullins-F-box) E3 ubiquitin ligase complexes, is located in this region. To evaluate the impact of FBXO25 removal, we established Fbxo25 knockout mice and characterized their phenotype. Both heterozygous (Het) and homozygous (Homo) Fbxo25 knockout mice are fertile and develop normally. Compared with wild-type (WT) littermates, Fbxo25 knockout mice exhibited comparable behaviors in the aspects of locomotion, emotion, social interaction, and aggression; notably, Homo Fbxo25 displayed excessive repetitive behavior and enhanced spatial learning. Given that FBXO25 is highly expressed in the hippocampus, we found reduced dendritic complexity in the granule cells of the dentate gyrus of both Het and Homo Fbxo25 knockout mice and increased dendritic spines in Het Fbxo25 knockout mice. Additionally, altered hippocampal protein expressions were noticed in knockout mice. Comparing the hippocampal protein and mRNA profiles, we identified increased GluN2A, mGluR5, ERK, and ARC proteins with unchanged mRNA expression in the Homo Fbxo25 knockout mice, suggesting the substrates of FBXO25-mediated protein degradation that impact the synaptic transmission and are relevant to the pathogenesis of ASD.