Biochemical, molecular and behavioral phenotypes of Rab3A mutations in the mouse

S Yang; M Farias; D Kapfhamer; J Tobias; G Grant; T Abel; M Bućan

doi:10.1111/j.1601-183X.2006.00235.x

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Biochemical, molecular and behavioral phenotypes of Rab3A mutations in the mouse

Journal article

Open access

Peer reviewed

Biochemical, molecular and behavioral phenotypes of Rab3A mutations in the mouse

S Yang, M Farias, D Kapfhamer, J Tobias, G Grant, T Abel and M Bućan

Genes, brain and behavior, Vol.6(1), pp.77-96

02/2007

DOI: 10.1111/j.1601-183X.2006.00235.x

PMCID: PMC2914309

PMID: 16734774

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Abstract

Ras-associated binding (Rab) protein 3A is a neuronal guanosine triphosphate (GTP)-binding protein that binds synaptic vesicles and regulates synaptic transmission. A mouse mutant, earlybird (Ebd) , with a point mutation in the GTP-binding domain of Rab3A (D77G), exhibits anomalies in circadian behavior and homeostatic response to sleep loss. Here, we show that the D77G substitution in the Ebd allele causes reduced GTP and GDP binding, whereas GTPase activity remains intact, leading to reduced protein levels of both Rab3A and rabphilin3A. Expression profiling of the cortex and hippocampus of Ebd and Rab3a -deficient mice revealed subtle differences between wild-type and mutant mice. Although mice were backcrossed for three generations to a C57BL/6J background, the most robust changes at the transcriptional level between Rab3a −/− and Rab3a +/+ mice were represented by genes from the 129/Sv-derived chromosomal region surrounding the Rab3a gene. These results showed that differences in genetic background have a stronger effect on gene expression than the mutations in the Rab3a gene. In behavioral tests, the Ebd/Ebd mice showed a more pronounced mutant phenotype than the null mice; Ebd/Ebd have reduced anxiety-like behavior in the elevated zero-maze test, reduced response to stress in the forced swim test and a deficit in cued fear conditioning (FC), whereas Rab3a −/− showed only a deficit in cued FC. Our data implicate Rab3A in learning and memory as well as in the regulation of emotion. A combination of forward and reverse genetics has provided multiple alleles of the Rab3a gene; our studies illustrate the power and complexities of the parallel analysis of these alleles at the biochemical, molecular and behavioral levels.

Rab3A

microarray

Behavior

GTPase

mouse mutant

Details

Title: Subtitle: Biochemical, molecular and behavioral phenotypes of Rab3A mutations in the mouse
Creators: S Yang - Department of Genetics, University of Pennsylvania, Philadelphia, PA
M Farias - Department of Genetics, University of Pennsylvania, Philadelphia, PA
D Kapfhamer - Department of Genetics, University of Pennsylvania, Philadelphia, PA
J Tobias - Penn Center for Bioinformatics, University of Pennsylvania, Philadelphia, PA, USA
G Grant - Department of Genetics, University of Pennsylvania, Philadelphia, PA
T Abel - Department of Biology, University of Pennsylvania, Philadelphia, PA, USA
M Bućan - Department of Genetics, University of Pennsylvania, Philadelphia, PA
Resource Type: Journal article
Publication Details: Genes, brain and behavior, Vol.6(1), pp.77-96
DOI: 10.1111/j.1601-183X.2006.00235.x
PMID: 16734774
PMCID: PMC2914309
ISSN: 1601-1848
eISSN: 1601-183X
Language: English
Date published: 02/2007
Academic Unit: Molecular Physiology and Biophysics; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
Record Identifier: 9984065732502771

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