title: Interaction of NOS1AP with the NOS-I PDZ domain: Implications for schizophrenia-related alterations in dendritic morphology.
abstract: Schizophrenia involves morphological brain changes, including changes in synaptic plasticity and altered dendritic development. Amongst the most promising candidate molecules for schizophrenia are neuronal nitric oxide (NO) synthase (NOS-I, also known as nNOS) and its adapter protein NOS1AP (previously named CAPON). However, the precise molecular mechanisms by which NOS-I and NOS1AP affect disease pathology remain to be resolved. Interestingly, overexpression of NOS1AP affects dendritic morphology, possibly through increased association with the NOS-I PDZ domain. To investigate the effect of NOS1AP on dendritic morphology we overexpressed different NOS1AP isoforms, NOS1AP deletion mutants and the aminoterminal 133 amino acids of NOS-I (NOS-IN133) containing an extended PDZ domain. We examined the interaction of the overexpressed constructs with endogenous NOS-I by co-immunoprecipitation and the consequences of increased NOS-I/NOS1AP PDZ interaction in primary cultures of hippocampal and cortical neurons from C57BL/6J mice. Neurons overexpressing NOS1AP isoforms or deletion mutants showed highly altered spine morphology and excessive growth of filopodia-like protrusions. Sholl analysis of immunostained primary cultured neurons revealed that dendritic branching was mildly affected by NOS1AP overexpression. Our results hint towards an involvement of NOS-I/NOS1AP interaction in the regulation of dendritic spine plasticity. As altered dendritic spine development and filopodial outgrowth are important neuropathological features of schizophrenia, our findings may provide insight into part of the molecular mechanisms involved in brain morphology alterations observed in schizophrenia. As the NOS-I/NOS1AP interface can be targeted by small molecules, our findings ultimately might help to develop novel treatment strategies for schizophrenia patients.
authors: Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital of Frankfurt, 60528 Frankfurt am Main, Germany; Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, 97080 Würzburg, Germany; Graduate School of Life Sciences, University of Würzburg, 97080 Würzburg, Germany.
authors: Esin
authors: E
authors: Candemir
authors: Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, 97080 Würzburg, Germany.
authors: Leonie
authors: L
authors: Kollert
authors: Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital of Frankfurt, 60528 Frankfurt am Main, Germany; Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, 97080 Würzburg, Germany.
authors: Lena
authors: L
authors: Weißflog
authors: Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, 97080 Würzburg, Germany.
authors: Maria
authors: M
authors: Geis
authors: Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, 97080 Würzburg, Germany.
authors: Antje
authors: A
authors: Müller
authors: Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital of Frankfurt, 60528 Frankfurt am Main, Germany; Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, 97080 Würzburg, Germany.
authors: Antonia M
authors: AM
authors: Post
authors: Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, 97080 Würzburg, Germany; Division of Neuropsychopharmacology, Department of Psychology, University of Tartu, Ravila 14A, Tartu 50411 Estonia.
authors: Aet
authors: A
authors: O'Leary
authors: Division of Neuropsychopharmacology, Department of Psychology, University of Tartu, Ravila 14A, Tartu 50411 Estonia.
authors: Jaanus
authors: J
authors: Harro
authors: Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital of Frankfurt, 60528 Frankfurt am Main, Germany; Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, 97080 Würzburg, Germany.
authors: Andreas
authors: A
authors: Reif
authors: Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital of Frankfurt, 60528 Frankfurt am Main, Germany; Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital of Würzburg, 97080 Würzburg, Germany. Electronic address: florian.freudenberg@kgu.de.
authors: Florian
authors: F
authors: Freudenberg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000473:pathology; D049229:Dendritic Spines / Q000378:metabolism / Q000473:pathology*; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D051379:Mice; D009154:Mutation; D052248:Nitric Oxide Synthase Type I / Q000737:chemistry* / Q000378:metabolism*; D061251:Primary Cell Culture; D011485:Protein Binding; D012559:Schizophrenia / Q000378:metabolism* / Q000473:pathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C110667:Nos1ap protein, mouse; D052248:Nitric Oxide Synthase Type I
keywords: Dendrite development; Mouse;; NOS1AP; Nos1; PDZ domain; Spine plasticity