International Meeting for Autism Research: The Impact of Gabrb3 Expression Variation On Autism Spectrum Disorder Related Phenotypes in Mouse

The Impact of Gabrb3 Expression Variation On Autism Spectrum Disorder Related Phenotypes in Mouse

Friday, May 21, 2010
Franklin Hall B Level 4 (Philadelphia Marriott Downtown)
3:00 PM
L. Herzing , Pediatrics, Program in Human Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL
S. Zeng , Pediatrics, Program in Human Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL
N. Chiu , Pediatrics, Program in Human Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL
M. Yasvoina , Pediatrics, Program in Human Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL
K. Kugle , Pediatrics, Program in Human Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL
Background: Several lines of evidence support a link between GABRB3, a GABA receptor subunit, and autism spectrum disorders. Total or conditional loss of this gene results in frequent post-natal lethality in mouse, with survivors exhibiting seizures and behavioral disorders. In contrast, haploinsufficiency results in variable gene expression and mild phenotypes that are gender, age and deletion parent-of-origin dependent. 

Objectives: To determine the phenotypic consequences of intermediate levels of Gabrb3 expression.

Methods: ShRNA-mediated Gabrb3-knockdown animals were generated on a C57Bl/6 background. Behavioral phenotypes were assessed in these, heterozygous gene knockout and wild-type control animals using standard protocols, including activity (wheel-running), anxiety (open field), exploratory (place preference & T-maze), socialization (interest, preference & memory: tethered & free interactions) and perseveration (radial maze).  

Results: As expected, both Gabrb3-knockdown (KD) and heterozygous knockout  (+/-) animals show behavioral differences from wild-type C57Bl/6 animals, with Gabrb3-KD animals exhibiting a phenotypic spectrum intermediate between Gabrb3+/- and total-knockout (KO) animals. Post-natal lethality or gender imbalance in KD animals is not evident, but cannot be ruled out in the founder generation due to small numbers. Unlike Gabrb3+/- animals, Gabrb3-KD animals exhibit hyperactivity reminiscent of surviving KO animals, but they do not exhibit the severe seizures seen in KO animals.

Conclusions: Phenotypic analyses of sh-mediated Gabrb3 knockdown animals complement studies using knockout and haploinsufficiency models, while avoiding early lethality and parent-of-origin dependent complications.

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