title: Srgap3⁻/⁻ mice present a neurodevelopmental disorder with schizophrenia-related intermediate phenotypes.
abstract: 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.
authors: Department of Molecular Biology, Central Institute of Mental Health and Heidelberg University, Mannheim, Germany.
authors: Robert
authors: R
authors: Waltereit
authors: Uwe
authors: U
authors: Leimer
authors: Oliver
authors: O
authors: von Bohlen Und Halbach
authors: Jutta
authors: J
authors: Panke
authors: Sabine M
authors: SM
authors: Hölter
authors: Lillian
authors: L
authors: Garrett
authors: Karola
authors: K
authors: Wittig
authors: Miriam
authors: M
authors: Schneider
authors: Camie
authors: C
authors: Schmitt
authors: Julia
authors: J
authors: Calzada-Wack
authors: Frauke
authors: F
authors: Neff
authors: Lore
authors: L
authors: Becker
authors: Cornelia
authors: C
authors: Prehn
authors: Sergej
authors: S
authors: Kutscherjawy
authors: Volker
authors: V
authors: Endris
authors: Claire
authors: C
authors: Bacon
authors: Helmut
authors: H
authors: Fuchs
authors: Valérie
authors: V
authors: Gailus-Durner
authors: Stefan
authors: S
authors: Berger
authors: Kai
authors: K
authors: Schönig
authors: Jerzy
authors: J
authors: Adamski
authors: Thomas
authors: T
authors: Klopstock
authors: Irene
authors: I
authors: Esposito
authors: Wolfgang
authors: W
authors: Wurst
authors: Martin Hrabe
authors: MH
authors: de Angelis
authors: Gudrun
authors: G
authors: Rappold
authors: Thomas
authors: T
authors: Wieland
authors: Dusan
authors: D
authors: Bartsch
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D006849:Hydrocephalus / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism; D012919:Social Behavior; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein
chemical_list: D020690:GTPase-Activating Proteins; D009479:Neuropeptides; C484602:Rac1 protein, mouse; C516731:Srgap3 protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein