DOI: 10.1097/01.yic.0000405905.72859.06

,  

Issn Print: 0268-1315

Publication Date: 2011/09/01


Print

SrGAP3/MEGAP knockout mice express schizophrenia-related endophenotypes

R. Waltereit; U. Leimer; O. von Bohlen und Halbach; J. Panke; L. Garrett; K. Wittig; M. Schneider; C. Schmitt; J. Calzada-Wack; F. Neff; L. Becker; C. Prehn; S. Kutscherjawy; V. Baier; V. Endris; G. Rappold; H. Fuchs; V. Gailus-Durner; S. Berger; K. Schönig; J. Adamski; T. Klopstock; I. Esposito; W. Wieland; W. Wurst; M. Habré de Angelis; D. Bartsch

    loading  Checking for direct PDF access through Ovid

Excerpt

Objective: SRGAP3 is a Rho GTPase and negatively regulates RAC1, which in turn is involved in the actin cytoskeleton dynamics during brain development and synaptic plasticity. SrGAP3 is located on chromosomal region 3p25, which is a highly increased susceptibility region for schizophrenia. Here we investigated the phenotype of mice with homozygous deletion of SrGAP3−/−.
Methods: We generated mice carrying a stop codon in exon 3 of SrGAP3 by gene targeting. SrGAP3−/− animals are viable. We assessed the phenotype of these mice with focus on neuroanatomy and behaviour.
Results: 10% of SrGAP3−/− mice develop a hydrocephalus and die at day 50. The 90% remaining SrGAP3−/− animals were further analysed in this study. About 75% of these mice have enlarged lateral ventricles. They have also enlarged white matter tracts and longer dendritic spines. They express increased RAC1 activity. SrGAP3−/− mice show less locomotor activity, have tics and are impaired in working memory. Long-term memory, however, is not impaired. Social behaviour is impaired in SrGAP3−/− mice. The mice are also sensitive to methylphenidate stimulation and are impaired in pre-pulse inhibition.
Conclusion: The findings demonstrate the role of SRGAP3 in RAC1 signalling, in the dynamics of the neuronal actin cytoskeleton and in neuronal functioning. The pattern of the phenotype matches in pivotal points to other mouse models of schizophrenia-related endophenotypes. The results support the importance of the 3p25 region and SrGAP3 for schizophrenia.
    loading  Loading Related Articles