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Research
Yann HERAULT
Centre National de la Recherche Scientifique
Corresponding Author
ORCiD: https://orcid.org/0000-0001-7049-6900
License:
This work is licensed under a CC BY 4.0 License. Read Full License
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.
Keywords
Copy number variation, neurodevelopment, intellectual disability, autism spectrum disorders, KCTD13, mouse model, recognition memory, preclinical treatment
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CURRENT STATUS: Published
View the published article at Molecular Autism.
No community comments so far
Editorial decision: Accept
On 11 Dec, 2020
Review #3 received
Received 09 Dec, 2020
Review #2 received
Received 06 Dec, 2020
Reviewer #3 agreed
On 01 Dec, 2020
Reviewer #2 agreed
On 30 Nov, 2020
Reviewers invited
Invitations sent on 30 Nov, 2020
Reviewer #1 agreed
On 30 Nov, 2020
Review #1 received
Received 30 Nov, 2020
Editor assigned
On 01 Nov, 2020
Submission checks complete
On 01 Nov, 2020
Editor invited
On 01 Nov, 2020
Version 1
Posted 25 Aug, 2020
No comments provided
Editorial decision: Major revision
On 23 Sep, 2020
Review #3 received
Received 22 Sep, 2020
Review #2 received
Received 17 Sep, 2020
Review #1 received
Received 11 Sep, 2020
Reviewer #3 agreed
On 09 Sep, 2020
Editor invited
On 28 Aug, 2020
Editor assigned
On 28 Aug, 2020
Reviewers invited
Invitations sent on 28 Aug, 2020
Reviewer #1 agreed
On 28 Aug, 2020
Reviewer #2 agreed
On 28 Aug, 2020
Submission checks complete
On 24 Aug, 2020
First submitted
On 14 Aug, 2020
Metrics
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PDF Downloads: ...
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Subject Areas
Cellular & Molecular Neuroscience
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A new preprint design is coming!
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See the published version of this preprint at Molecular Autism.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Yann HERAULT
Centre National de la Recherche Scientifique
Corresponding Author
ORCiD: https://orcid.org/0000-0001-7049-6900
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at Molecular Autism.
No community comments so far
Editorial decision: Accept
On 11 Dec, 2020
Review #3 received
Received 09 Dec, 2020
Review #2 received
Received 06 Dec, 2020
Reviewer #3 agreed
On 01 Dec, 2020
Reviewer #2 agreed
On 30 Nov, 2020
Reviewers invited
Invitations sent on 30 Nov, 2020
Reviewer #1 agreed
On 30 Nov, 2020
Review #1 received
Received 30 Nov, 2020
Editor assigned
On 01 Nov, 2020
Submission checks complete
On 01 Nov, 2020
Editor invited
On 01 Nov, 2020
Version 1
Posted 25 Aug, 2020
No comments provided
Editorial decision: Major revision
On 23 Sep, 2020
Review #3 received
Received 22 Sep, 2020
Review #2 received
Received 17 Sep, 2020
Review #1 received
Received 11 Sep, 2020
Reviewer #3 agreed
On 09 Sep, 2020
Editor invited
On 28 Aug, 2020
Editor assigned
On 28 Aug, 2020
Reviewers invited
Invitations sent on 28 Aug, 2020
Reviewer #1 agreed
On 28 Aug, 2020
Reviewer #2 agreed
On 28 Aug, 2020
Submission checks complete
On 24 Aug, 2020
First submitted
On 14 Aug, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cellular & Molecular Neuroscience
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Molecular Autism.
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.
Figure 1
Figure 2
Figure 3
Figure 4
This is a list of supplementary files associated with this preprint. Click to download.
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