RESEARCH ARTICLE

Phenotype analysis and rescue on female FVB.129-Fmr1 knockout mice

  • Stacy Nguy 2 ,
  • Maria Victoria Tejada-Simon , 1,2,3,4
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  • 1. Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX 77204, USA
  • 2. Department of Biology, University of Houston, Houston, TX 77204, USA
  • 3. Department of Psychology, University of Houston, Houston, TX 77204, USA
  • 4. Biology of Behavior Institute (BoBI), University of Houston, Houston, TX 77204, USA

Received date: 01 Jan 2016

Accepted date: 20 Feb 2016

Published date: 22 Mar 2016

Copyright

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg

Abstract

Fragile X syndrome (FXS) is the most common monogenic cause of intellectual disability and a cause for autism. FXS females report milder phenotypes and a lower rate of cognitive problems compared to males. This is most likely because most females are heterozygous, while males are hemizygous for the disease. Thus, most preclinical studies have been completed in males. As there is major interest in testing experimental drugs for FXS, it is imperative to determine whether females in animal models used for research, present behavioral alterations that might translate to humans in order to confirm that experimental drugs have an effect on both genders. In our study we describe behavioral phenotypes in homozygous FXS female mice developed on the FVB.129 background. We focused on detection of hippocampal-mediated cognitive abilities and other behaviors described for FXS. Our research shows that, while female FVB.129-Fmr1 knockout mice present normal learning, they have impaired memory, as well as susceptibility to audiogenic seizures. In agreement with previous reports in rodents and humans, significant levels of the small GTPase Rac1 were found in FXS female mice. Because Rac1 is involved in neuronal development, plasticity and behavior, we additionally aimed to pharmacologically inhibit Rac1 and determine whether observed phenotypes are rescued. Treatment of female FVB.129-Fmr1 knockout with a Rac1 inhibitor abolished behavioral deficits, bringing phenotypes to control levels. Our results suggest that female FVB.129-Fmr1 knockout mice display behavioral impairments that resemble FXS in humans. Moreover, those behavioral shortfalls might be associated with alteration of plasticity involving excessive Rac1 function, since pharmacological reduction of Rac1 normalizes previously altered phenotypes to control levels.

Cite this article

Stacy Nguy , Maria Victoria Tejada-Simon . Phenotype analysis and rescue on female FVB.129-Fmr1 knockout mice[J]. Frontiers in Biology, 2016 , 11(1) : 43 -52 . DOI: 10.1007/s11515-016-1391-5

Acknowledgements

This study was supported by the JérômeLeJeune Foundation (France), FRAXA Research Foundation (USA) and the Grants for the Enhancement and Advancement of Research – GEAR (UH) to M.V.T.S.
All institutional and national guidelines for the care and use of laboratory animals were followed. Our experiments were executed in agreement with the Public Health Service policies and the Animal Welfare Act, with animal used protocols approved by the University of Houston Institutional Animal Care and Use Committee (IACUC). Stacy Nguy and Maria V. Tejada-Simon, both declare that they have no conflict of interest.
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