WDR62 deficiency results in synaptic dysfunction and ASD-like behaviors in mice, which can be ameliorated by RA repletion

Abstract Background: Brain size abnormality is correlated with increased frequency of autism spectrum disorder (ASD) in offspring. Genetic analysis indicates that many heterozygous mutations of microcephaly-associated genes including WD repeat domain 62 (WDR62), are associated with ASD; however, biological evidence is still lacking.Methods: To investigate the association between WDR62 and ASD, we generated both Wdr62 conventional knockout (Wdr62 KO) and Nex-Cre conditional knockout (Wdr62 Nex-cKO) mice. We investigated and compared the behavioral alterations between these mice and their littermate controls. Morphological and electrophysiological analyses were adopted to explore the mechanism underlying the abnormal behaviors. Furthermore, all-trans retinoic acid (RA), a derivative of vitamin A, was tried to treat aberrant behaviors.Results: Our study showed that Wdr62 KO led to reduced brain size with impaired learning and memory, as well as ASD-like behaviors in mice. Interestingly, aberrant social interactions and repetitive behaviors were also observed in Wdr62 Nex-cKO mice, but no deficits in brain size, and learning and memory. Mechanically, we found that WDR62 regulated dendritic spinogenesis and excitatory synaptic transmission in cortical pyramidal neurons. Finally, we revealed that RA gavages could significantly alleviate ASD-like behaviors in WDR62 haploinsufficiency mice probably by complementing the expression of ASD and synapse-related genes. Limitations: RA oral gavage significantly alleviated ASD-like behavior in WDR62 haploinsufficiency mice, while whether RA supplement could ameliorate ASD-like behavior in WDR62 KO mice is unknown. In addition, it is not known that whether the content of RA in Wdr62 deficiency mice is changed. Conclusions: Our findings provide not only new insight into the roles of WDR62 in brain development, but also a new perspective for the relationship between microcephaly gene WDR62 and ASD etiology which will benefit clinical diagnosis and intervention of ASD.