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

Srgap3-/- mice present a neurodevelopmental disorder with schizophrenia-related intermediate phenotypes.

FASEB J. 26, 4418-4428 (2012)
DOI PMC
Mutations in the SRGAP3 gene residing on chromosome 3p25 have previously been associated with intellectual disability. Genome-wide association studies have also revealed SRGAP3, together with genes from the same cellular network, as risk genes for schizophrenia. SRGAP3 regulates cytoskeletal dynamics through the RHO protein RAC1. RHO proteins are known to be involved in cytoskeletal reorganization during brain development to control processes such as synaptic plasticity. To elucidate the importance of SRGAP3 in brain development, we generated Srgap3-knockout mice. Ten percent of these mice developed a hydrocephalus and died before adulthood. Surviving mice showed various neuroanatomical changes, including enlarged lateral ventricles, white matter tracts, and dendritic spines together with molecular changes, including an increased basal activity of RAC1. Srgap3(-/-) mice additionally exhibited a complex behavioral phenotype. Behavioral studies revealed an impaired spontaneous alternation and social behavior, while long-term memory was unchanged. The animals also had tics. Lower locomotor activity was observed in male Srgap3(-/-) only. Srgap3(-/-) mice showed increased methylphenidate stimulation in males and an impaired prepulse inhibition in females. Together, the results show neurodevelopmental aberration in Srgap3(-/-) mice, with many of the observed phenotypes matching several schizophrenia-related intermediate phenotypes. Mutations of SRGAP3 may thus contribute to various neurodevelopmental disorders.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter intellectual disability; hydrocephalus; knockout mouse; RHO proteins; polygenetic disease
Sprache englisch
Veröffentlichungsjahr 2012
HGF-Berichtsjahr 2012
ISSN (print) / ISBN 0892-6638
e-ISSN 1530-6860
Zeitschrift FASEB Journal
Quellenangaben Band: 26, Heft: 11, Seiten: 4418-4428 Artikelnummer: , Supplement: ,
Verlag Wiley
Verlagsort Bethesda, Md.
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Developmental Genetics (IDG)
Institute of Pathology (PATH)
Institute of Experimental Genetics (IEG)
Molekulare Endokrinologie und Metabolismus (MEM)
POF Topic(s) 30204 - Cell Programming and Repair
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30201 - Metabolic Health
Forschungsfeld(er) Genetics and Epidemiology
Enabling and Novel Technologies
PSP-Element(e) G-500500-001
G-500300-001
G-500600-003
G-500600-001
G-505600-001
PubMed ID 22820399
DOI 10.1096/fj.11-202317
Scopus ID 84868275867
Erfassungsdatum 2012-08-03
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