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Srgap3 –/– mice present a neurodevelopmental disorder with schizophrenia‐related intermediate phenotypes
Author(s) -
Waltereit Robert,
Leimer Uwe,
Halbach Oliver von Bohlen und,
Panke Jutta,
Hölter Sabine M.,
Garrett Lillian,
Wittig Karola,
Schneider Miriam,
Schmitt Camie,
CalzadaWack Julia,
Neff Frauke,
Becker Lore,
Prehn Cornelia,
Kutscherjawy Sergej,
Endris Volker,
Bacon Claire,
Fuchs Helmut,
GailusDurner Valérie,
Berger Stefan,
Schönig Kai,
Adamski Jerzy,
Klopstock Thomas,
Esposito Irene,
Wurst Wolfgang,
Angelis Martin Hrabě,
Rappold Gudrun,
Wieland Thomas,
Bartsch Dusan
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.11-202317
Subject(s) - phenotype , prepulse inhibition , biology , neurodevelopmental disorder , schizophrenia (object oriented programming) , neuroscience , lateral ventricles , dendritic spine , knockout mouse , gene , genetics , psychology , hippocampal formation , psychiatry
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.—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). www.fasebj.org