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NOMA-GAP/ARHGAP33 regulates synapse development and autistic-like behavior in the mouse

Molecular Psychiatry volume 20, pages 1120–1131 (2015)Cite this article

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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.

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Acknowledgements

We thank E Tarland for valuable technical support with the animal behavior experiments and for Supplementary Figure S4A and J Schüler for advice on microscopy and E Bessa for help during the revision process. This study was supported by the DFG: RO3497/3-1 (M Rosário); EXC257 NeuroCure (M Rivalan, YW, NR, SAS and VT); SFB665 and Heisenberg program (VT). In addition, SS was funded by the Charité PhD Scholarship and equipment used by US was partially funded by the Sonnenfeld Stiftung.

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Authors and Affiliations

  1. Dendritic Development, Institute of Cell and Neurobiology, Charité Universitätsmedizin Berlin, Berlin, Germany

    S Schuster, D Lajkó & M Rosário

  2. Institute of Cognitive Neurobiology, Humboldt University Berlin and Berlin Mouse Clinic for Neurology and Psychiatry, Charité Universitätsmedizin, Berlin, Germany

    M Rivalan & Y Winter

  3. Ionic Current Development, Institute of Cell and Neurobiology, Charité Universitätsmedizin Berlin, Berlin, Germany

    U Strauss & L Stoenica

  4. Neuroscience, NeuroCure—NWFZ, Charité Universitätsmedizin Berlin, Berlin, Germany

    T Trimbuch & C Rosenmund

  5. Molecular Neurobiology and Genetics, NeuroCure—NWFZ, Charité Universitätsmedizin Berlin, Berlin, Germany

    N Rademacher & S A Shoichet

  6. Cortical Development, Institute of Cell and Neurobiology, Charité Universitätsmedizin Berlin, Berlin, Germany

    S Parthasarathy, D Lajkó & V Tarabykin

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  1. S Schuster
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Correspondence to M Rosário.

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Schuster, S., Rivalan, M., Strauss, U. et al. NOMA-GAP/ARHGAP33 regulates synapse development and autistic-like behavior in the mouse. Mol Psychiatry 20, 1120–1131 (2015). https://doi.org/10.1038/mp.2015.42

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