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Fgf9 Y162C Mutation Alters Information Processing and Social Memory in Mice

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Abstract

In neuropsychiatric diseases, such as major depression and anxiety, pathogenic vulnerability is partially dictated by a genetic predisposition. The search continues to define this genetic susceptibility and establish new genetic elements as potential therapeutic targets. The fibroblast growth factors (FGFs) could be interesting in this regard. This family of signaling molecules plays important roles in development while also functioning within the adult. This includes effects on aspects of brain function such as neurogenesis and synapse formation. Of this family, Fgf9 is expressed in the adult brain, but its functional role is less well defined. In this study, we examined the role of Fgf9 in different brain functions by analyzing the behavior of Fgf9 Y162C mutant mice, an Fgf9 allele without the confounding systemic effects of other Fgf9 genetic models. Here, we show that this mutation caused altered locomotor and exploratory reactivity to novel, mildly stressful environments. In addition, mutants showed heightened acoustic startle reactivity as well as impaired social discrimination memory. Notably, there was a substantial decrease in the level of adult olfactory bulb neurogenesis with no difference in hippocampal neurogenesis. Collectively, our findings indicate a role for the Fgf9 Y162C mutation in information processing and perception of aversive situations as well as in social memory. Thus, genetic alterations in Fgf9 could increase vulnerability to developing neuropsychiatric disease, and we propose the Fgf9 Y162C mutant mice as a valuable tool to study the predictive etiological aspects.

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Acknowledgements

The authors thank all the technicians from the German Mouse Clinic: Jan Einicke, Birgit Frankenberger, Sandra Geißler, Christine Hollauer, Maria Kugler, Simon Orth, Yvonne Sonntag, and Bettina Sperling as well as Erika Bürkle and Monika Stadler for the breeding of the cohorts. Thanks also to Amy Gorol for careful editing of the manuscript and to Hugh Garrett for the graphic artwork. This work has been funded by the German Federal Ministry of Education and Research to the GMC (Infrafrontier grant 01KX1012), to the German Center for Diabetes Research (DZD e.V.), the German Federal Ministry of Education and Research (BMBF) through the Integrated Network MitoPD (Mitochondrial endophenotypes of Morbus Parkinson), under the auspices of the e:Med Programme (grant 031A430E) as well as by the Helmholtz Portfolio Theme ‘Supercomputing and Modelling for the Human Brain’ (SMHB) to WW.

Author information

Author notes

  1. Oliver Puk

    Present address: CeGaT GmbH, Paul-Ehrlich-Str. 23, 72076, Tübingen, Germany

  2. Alexander Bohla

    Present address: Satorius Stedim Biotech, Aubagne, France

Authors and Affiliations

  1. Institutes of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany

    Lillian Garrett, Oliver Puk, Wolfgang Wurst, Jochen Graw & Sabine M. Hölter

  2. German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany

    Lillian Garrett, Lore Becker, Jan Rozman, Oliver Puk, Tobias Stoeger, Ali Önder Yildirim, Alexander Bohla, Oliver Eickelberg, Wolfgang Hans, Cornelia Prehn, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabě de Angelis, Jochen Graw & Sabine M. Hölter

  3. Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany

    Lore Becker, Jan Rozman, Wolfgang Hans, Cornelia Prehn, Jerzy Adamski, Helmut Fuchs, Valerie Gailus-Durner & Martin Hrabě de Angelis

  4. German Center for Diabetes Research (DZD), Neuherberg, Germany

    Jan Rozman & Martin Hrabě de Angelis

  5. Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, The German Center for Lung Research (DZL), German Research Center for Environmental Health, Neuherberg, Germany

    Tobias Stoeger, Ali Önder Yildirim, Alexander Bohla & Oliver Eickelberg

  6. Experimental Genetics, Faculty of Life and Food Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Munich, Germany

    Jerzy Adamski & Martin Hrabě de Angelis

  7. Department of Neurology, Friedrich-Baur Institute, Klinikum der Ludwig-Maximilians-Universität München, Munich, Germany

    Thomas Klopstock

  8. Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE), Munich, Germany

    Thomas Klopstock & Wolfgang Wurst

  9. Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität München, Munich, Germany

    Thomas Klopstock & Wolfgang Wurst

  10. Institute of Molecular Psychiatry, Medical Faculty, Universität Bonn, Bonn, Germany

    Ildikó Rácz & Andreas Zimmer

  11. Molecular Nutritional Medicine, Faculty of Life and Food Sciences Weihenstephan, Technische Universität München, Munich, Germany

    Martin Klingenspor

  12. Developmental Genetics, Faculty of Life and Food Sciences Weihenstephan, Technische Universität München, Freising-Weihenstephan, Munich, Germany

    Wolfgang Wurst

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  1. Lillian Garrett
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Correspondence to Sabine M. Hölter.

Ethics declarations

Mice were kept under specific pathogen-free conditions at the Helmholtz Center Munich. The use of animals was in accordance with the German Law of Animal Protection, the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research, and the tenets of the Declaration of Helsinki. All tests performed and described here were approved for the ethical treatment of animals by the responsible authority of the Regierung von Oberbayern (Government of Upper Bavaria).

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Supplemental Figure 1

Negative controls with omission of primary antibodies showing no positive staining in A: the dentate gyrus (for PCNA, similar lack of staining seen with omission of DCX), B: rostral migratory stream/subventricular zone (for PCNA) and C: olfactory bulb granular cell layer (for DCX). Scale bar = 100 μm (GIF 118 kb)

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Garrett, L., Becker, L., Rozman, J. et al. Fgf9 Y162C Mutation Alters Information Processing and Social Memory in Mice. Mol Neurobiol 55, 4580–4595 (2018). https://doi.org/10.1007/s12035-017-0659-3

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