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Mouse model of Timothy syndrome recapitulates triad of autistic traits.

Publication ,  Journal Article
Bader, PL; Faizi, M; Kim, LH; Owen, SF; Tadross, MR; Alfa, RW; Bett, GCL; Tsien, RW; Rasmusson, RL; Shamloo, M
Published in: Proceedings of the National Academy of Sciences of the United States of America
September 2011

Autism and autism spectrum disorder (ASD) typically arise from a mixture of environmental influences and multiple genetic alterations. In some rare cases, such as Timothy syndrome (TS), a specific mutation in a single gene can be sufficient to generate autism or ASD in most patients, potentially offering insights into the etiology of autism in general. Both variants of TS (the milder TS1 and the more severe TS2) arise from missense mutations in alternatively spliced exons that cause the same G406R replacement in the Ca(V)1.2 L-type calcium channel. We generated a TS2-like mouse but found that heterozygous (and homozygous) animals were not viable. However, heterozygous TS2 mice that were allowed to keep an inverted neomycin cassette (TS2-neo) survived through adulthood. We attribute the survival to lowering of expression of the G406R L-type channel via transcriptional interference, blunting deleterious effects of mutant L-type channel overactivity, and addressed potential effects of altered gene dosage by studying Ca(V)1.2 knockout heterozygotes. Here we present a thorough behavioral phenotyping of the TS2-neo mouse, capitalizing on this unique opportunity to use the TS mutation to model ASD in mice. Along with normal general health, activity, and anxiety level, TS2-neo mice showed markedly restricted, repetitive, and perseverative behavior, altered social behavior, altered ultrasonic vocalization, and enhanced tone-cued and contextual memory following fear conditioning. Our results suggest that when TS mutant channels are expressed at levels low enough to avoid fatality, they are sufficient to cause multiple, distinct behavioral abnormalities, in line with the core aspects of ASD.

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Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

September 2011

Volume

108

Issue

37

Start / End Page

15432 / 15437

Related Subject Headings

  • Vocalization, Animal
  • Ultrasonics
  • Syndactyly
  • Social Behavior
  • Motor Activity
  • Mice, Mutant Strains
  • Mice, Knockout
  • Mice
  • Memory
  • Maze Learning
 

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Bader, P. L., Faizi, M., Kim, L. H., Owen, S. F., Tadross, M. R., Alfa, R. W., … Shamloo, M. (2011). Mouse model of Timothy syndrome recapitulates triad of autistic traits. Proceedings of the National Academy of Sciences of the United States of America, 108(37), 15432–15437. https://doi.org/10.1073/pnas.1112667108
Bader, Patrick L., Mehrdad Faizi, Leo H. Kim, Scott F. Owen, Michael R. Tadross, Ronald W. Alfa, Glenna C. L. Bett, Richard W. Tsien, Randall L. Rasmusson, and Mehrdad Shamloo. “Mouse model of Timothy syndrome recapitulates triad of autistic traits.Proceedings of the National Academy of Sciences of the United States of America 108, no. 37 (September 2011): 15432–37. https://doi.org/10.1073/pnas.1112667108.
Bader PL, Faizi M, Kim LH, Owen SF, Tadross MR, Alfa RW, et al. Mouse model of Timothy syndrome recapitulates triad of autistic traits. Proceedings of the National Academy of Sciences of the United States of America. 2011 Sep;108(37):15432–7.
Bader, Patrick L., et al. “Mouse model of Timothy syndrome recapitulates triad of autistic traits.Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 37, Sept. 2011, pp. 15432–37. Epmc, doi:10.1073/pnas.1112667108.
Bader PL, Faizi M, Kim LH, Owen SF, Tadross MR, Alfa RW, Bett GCL, Tsien RW, Rasmusson RL, Shamloo M. Mouse model of Timothy syndrome recapitulates triad of autistic traits. Proceedings of the National Academy of Sciences of the United States of America. 2011 Sep;108(37):15432–15437.
Journal cover image

Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

September 2011

Volume

108

Issue

37

Start / End Page

15432 / 15437

Related Subject Headings

  • Vocalization, Animal
  • Ultrasonics
  • Syndactyly
  • Social Behavior
  • Motor Activity
  • Mice, Mutant Strains
  • Mice, Knockout
  • Mice
  • Memory
  • Maze Learning