title: NOMA-GAP/ARHGAP33 regulates synapse development and autistic-like behavior in the mouse.
abstract: Neuropsychiatric developmental disorders, such as autism spectrum disorders (ASDs) and schizophrenia, are typically characterized by alterations in social behavior and have been linked to aberrant dendritic spine and synapse development. Here we show, using genetically engineered mice, that the Cdc42 GTPase-activating multiadaptor protein, NOMA-GAP, regulates autism-like social behavior in the mouse, as well as dendritic spine and synapse development. Surprisingly, we were unable to restore spine morphology or autism-associated social behavior in NOMA-GAP-deficient animals by Cre-mediated deletion of Cdc42 alone. Spine morphology can be restored in vivo by re-expression of wild-type NOMA-GAP or a mutant of NOMA-GAP that lacks the RhoGAP domain, suggesting that other signaling functions are involved. Indeed, we show that NOMA-GAP directly interacts with several MAGUK (membrane-associated guanylate kinase) proteins, and that this modulates NOMA-GAP activity toward Cdc42. Moreover, we demonstrate that NOMA-GAP is a major regulator of PSD-95 in the neocortex. Loss of NOMA-GAP leads to strong upregulation of serine 295 phosphorylation of PSD-95 and moreover to its subcellular mislocalization. This is associated with marked loss of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and defective synaptic transmission, thereby providing a molecular basis for autism-like social behavior in the absence of NOMA-GAP.
authors: Dendritic Development, Institute of Cell and Neurobiology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors: S
authors: S
authors: Schuster
authors: Institute of Cognitive Neurobiology, Humboldt University Berlin and Berlin Mouse Clinic for Neurology and Psychiatry, Charité Universitätsmedizin, Berlin, Germany.
authors: M
authors: M
authors: Rivalan
authors: Ionic Current Development, Institute of Cell and Neurobiology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors: U
authors: U
authors: Strauss
authors: Ionic Current Development, Institute of Cell and Neurobiology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors: L
authors: L
authors: Stoenica
authors: Neuroscience, NeuroCure-NWFZ, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors: T
authors: T
authors: Trimbuch
authors: Molecular Neurobiology and Genetics, NeuroCure-NWFZ, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors: N
authors: N
authors: Rademacher
authors: Cortical Development, Institute of Cell and Neurobiology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors: S
authors: S
authors: Parthasarathy
authors: Dendritic Development, Institute of Cell and Neurobiology, Charité Universitätsmedizin Berlin, Berlin, Germany.|Cortical Development, Institute of Cell and Neurobiology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors: D
authors: D
authors: Lajkó
authors: Neuroscience, NeuroCure-NWFZ, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors: C
authors: C
authors: Rosenmund
authors: Molecular Neurobiology and Genetics, NeuroCure-NWFZ, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors: S A
authors: SA
authors: Shoichet
authors: Institute of Cognitive Neurobiology, Humboldt University Berlin and Berlin Mouse Clinic for Neurology and Psychiatry, Charité Universitätsmedizin, Berlin, Germany.
authors: Y
authors: Y
authors: Winter
authors: Cortical Development, Institute of Cell and Neurobiology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors: V
authors: V
authors: Tarabykin
authors: Dendritic Development, Institute of Cell and Neurobiology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors: M
authors: M
authors: Rosário
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001522:Behavior, Animal / Q000502:physiology*; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D051528:Guanylate Kinases / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019579:Neocortex / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D015398:Signal Transduction; D012919:Social Behavior; D013569:Synapses / Q000378:metabolism / Q000502:physiology*
chemical_list: D020690:GTPase-Activating Proteins; D018091:Receptors, AMPA; C475478:TCGAP protein, mouse; C085379:rho GTPase-activating protein; D051528:Guanylate Kinases