Abstract
BackgroundGene copy number variants play an important role in the occurrence of neurodevelopmental disorders. Particularly, the deletion of the 16p11.2 locus is associated with autism spectrum disorder, intellectual disability, and several other features. Earlier studies highlighted the implication of Kctd13 genetic imbalance in 16p11.2 deletion through the regulation of the RHOA pathway.MethodsHere, we generated a new mouse model with a small deletion of two key exons in Kctd13. Then, we targeted the RHOA pathway to rescue the cognitive phenotypes of the Kctd13 and 16p11.2 deletion mouse models in a pure genetic background. We used a chronic administration of fasudil (HA1077), an inhibitor of the Rho-associated protein kinase, for six weeks in mouse models carrying a heterozygous inactivation of Kctd13, or the deletion of the entire 16p11.2 BP4-BP5 homologous region.ResultsWe found that the small Kctd13 heterozygous deletion induced a cognitive phenotype similar to the whole deletion of the 16p11.2 homologous region, in the Del/+ mice. We then showed that chronic fasudil treatment can restore object recognition memory in adult heterozygous mutant mice for Kctd13 and for 16p11.2 deletion. In addition, learning and memory improvement occurred in parallel to change in the RHOA pathway.LimitationsThe Kcdt13 mutant line does not recapitulate all the phenotypes found in the 16p11.2 Del/+ model. In particular, the locomotor activity was not altered at 12 and 18 weeks of age and the object location memory was not defective in 18-week old mutants. Similarly, the increase in locomotor activity was not modified by the treatment in the 16p11.2 Del/+ mouse model, suggesting that other loci were involved in such defects. Rescue was observed only after four weeks of treatment but no long-term experiment has been carried out so far. Finally, we did not check the social behaviour, which requires working in another hybrid genetic background.ConclusionThese findings confirm KCTD13 as one target gene causing cognitive deficits in 16p11.2 deletion patients, and the relevance of the RHOA pathway as a therapeutic path for 16p11.2 deletion. In addition, they reinforce the contribution of other gene(s) involved in cognitive defects found in the 16p11.2 models in older mice.
Highlights
Genetic copy number variants of the 16p11.2 locus are an important risk factor for multiple neurodevelopmental disorders [1,2,3,4,5]
We evaluated its learning and memory behaviour at 12 weeks of age in the open field, novel object location (NOL) and novel object recognition (NOR), and compared the results obtained with the characterization of the 16p11.2 Del/+ model (Fig. 2)
We found that the Kctd13+/− mice experienced a similar habituation to the control individuals (Additional file 1: Supplementary Fig. 2A)
Summary
Genetic copy number variants of the 16p11.2 locus are an important risk factor for multiple neurodevelopmental disorders [1,2,3,4,5]. A study conducted in 2011 found a microdeletion of the 118 kb region, containing MVP, SEZ6L2, CDIPT, ASPHD1 and KCTD13 inside the 16p11.2 genetic interval, linked to Autism Spectrum Disorder in a family over three generations [17]. This MVP-KCTD13 subregion should play a potential key role in the neuropsychiatric features linked to 16p11.2 rearrangement. Earlier studies highlighted the implication of Kctd genetic imbalance in 16p11.2 deletion through the regulation of the RHOA pathway
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