Targeting the RHOA pathway improves learning and memory in adult Kctd13 and 16p11.2 deletion mouse models - Archive ouverte HAL
Article Dans Une Revue Molecular Autism Année : 2021

Targeting the RHOA pathway improves learning and memory in adult Kctd13 and 16p11.2 deletion mouse models

Résumé

Background Gene copy number variants have an important role in the appearance 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 the 16p11.2 deletion through the regulation of the RHOA pathway. Methods Here, we generated a new mouse models 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 (ROCK), for several days, in mouse models carrying a heterozygous inactivation of Kctd13 , or the deletion of the entire 16p11.2 BP4-BP5 homologous region. Results We found that the small Kctd13 heterozygous deletion induced similar cognitive phenotype to the whole deletion of the 16p11.2 homologous region, in the Del/+ mice. Then we showed the chronic fasudil treatment can restore object recognition memory in adult heterozygous mutant mice for Kctd13 and for 16p11.2 deletion. In addition, the learning and memory improvement was parallel to change in the RHOA pathway. Limitations: The 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 weeks old mutants. Similarly, the increased in locomotor activity was not modified by the treatment in the 16p11.2 Del/+ mouse model suggesting other loci involved in such defects. Then, the rescue was only observed after four weeks of treatment but no long term experiment has been done so far. Finally we did not check the social behaviour that require to work in another hybrid genetic background. Conclusion These 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 the 16p11.2 deletion. Nevertheless, they reinforce the contribution of other gene(s) involved in cognitive defects found in the 16p11.2 models in older mice.
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hal-03187247 , version 1 (27-11-2021)

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Sandra Martin Lorenzo, Valérie Nalesso, Claire Chevalier, Marie-Christine Birling, Yann Hérault. Targeting the RHOA pathway improves learning and memory in adult Kctd13 and 16p11.2 deletion mouse models. Molecular Autism, 2021, 12 (1), ⟨10.1186/s13229-020-00405-7⟩. ⟨hal-03187247⟩
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