Hippocampal overexpression of NOS1AP promotes endophenotypes related to mental disorders
Florian Freudenberg,
Esin Candemir,
Xufeng Chen,
Li-Li Li,
Dilhan Esen-Sehir,
Nicole Schenk,
Makoto Kinoshita,
Lena Grünewald,
Veronika Frerichs,
Nikolai Fattakhov,
Jessica Manchen,
Solmaz Bikas,
Anita Kumar,
Aet OLeary,
David A. Slattery,
Jakob von Engelhardt,
Michael J. Courtney,
Andreas Reif
Affiliations
Florian Freudenberg
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany; Corresponding author. Dr. Florian Freudenberg, Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Heinrich-Hoffmann-Str. 10, 60528 Frankfurt am Main, Germany, Phone: +49 69 6301-85665, Fax: +49 69 6301-84481
Esin Candemir
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany; Graduate School of Life Sciences, University of Würzburg, Würzburg, Germany
Xufeng Chen
Institute of Pathophysiology, Mainz University Medical Center, Mainz, Germany
Li-Li Li
Neuronal Signalling Laboratory, Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
Dilhan Esen-Sehir
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany; The Faculty of Biological Sciences, Goethe University, Frankfurt, Germany
Nicole Schenk
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany
Makoto Kinoshita
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany
Lena Grünewald
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany
Veronika Frerichs
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany
Nikolai Fattakhov
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany
Jessica Manchen
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany
Solmaz Bikas
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany; The Faculty of Biological Sciences, Goethe University, Frankfurt, Germany
Anita Kumar
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany; The Faculty of Biological Sciences, Goethe University, Frankfurt, Germany
Aet OLeary
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany
David A. Slattery
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany
Jakob von Engelhardt
Institute of Pathophysiology, Mainz University Medical Center, Mainz, Germany
Michael J. Courtney
Neuronal Signalling Laboratory, Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
Andreas Reif
Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany
Background: Nitric oxide synthase 1 adaptor protein (NOS1AP; previously named CAPON) is linked to the glutamatergic postsynaptic density through interaction with neuronal nitric oxide synthase (nNOS). NOS1AP and its interaction with nNOS have been associated with several mental disorders. Despite the high levels of NOS1AP expression in the hippocampus and the relevance of this brain region in glutamatergic signalling as well as mental disorders, a potential role of hippocampal NOS1AP in the pathophysiology of these disorders has not been investigated yet. Methods: To uncover the function of NOS1AP in hippocampus, we made use of recombinant adeno-associated viruses to overexpress murine full-length NOS1AP or the NOS1AP carboxyterminus in the hippocampus of mice. We investigated these mice for changes in gene expression, neuronal morphology, and relevant behavioural phenotypes. Findings: We found that hippocampal overexpression of NOS1AP markedly increased the interaction of nNOS with PSD-95, reduced dendritic spine density, and changed dendritic spine morphology at CA1 synapses. At the behavioural level, we observed an impairment in social memory and decreased spatial working memory capacity. Interpretation: Our data provide a mechanistic explanation for a highly selective and specific contribution of hippocampal NOS1AP and its interaction with the glutamatergic postsynaptic density to cross-disorder pathophysiology. Our findings allude to therapeutic relevance due to the druggability of this molecule. Funding: This study was funded in part by the DFG, the BMBF, the Academy of Finland, the NIH, the Japanese Society of Clinical Neuropsychopharmacology, the Ministry of Education of the Russian Federation, and the European Community.
