Fgf9Y162C Mutation Alters Information Processing and Social Memory in Mice

  • Lillian Garrett
  • Lore Becker
  • Jan Rozman
  • Oliver Puk
  • Tobias Stoeger
  • Ali Önder Yildirim
  • Alexander Bohla
  • Oliver Eickelberg
  • Wolfgang Hans
  • Cornelia Prehn
  • Jerzy Adamski
  • Thomas Klopstock
  • Ildikó Rácz
  • Andreas Zimmer
  • Martin Klingenspor
  • Helmut Fuchs
  • Valerie Gailus-Durner
  • Wolfgang Wurst
  • Martin Hrabě de Angelis
  • Jochen Graw
  • Sabine M. Hölter
Article

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 Fgf9Y162C 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 Fgf9Y162C 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 Fgf9Y162C mutant mice as a valuable tool to study the predictive etiological aspects.

Keywords

Fibroblast growth factor 9 Neuropsychiatric disease Mice Brain Adult neurogenesis 

Notes

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.

Compliance with Ethical Standards

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).

Supplementary material

12035_2017_659_Fig8_ESM.gif (118 kb)
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)

12035_2017_659_MOESM1_ESM.tif (2.3 mb)
High resolution image (TIFF 2325 kb)

References

  1. 1.
    Cross-Disorder Group of the Psychiatric Genomics C, Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM, Perlis RH, Mowry BJ et al (2013) Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet 45(9):984–994. doi:10.1038/ng.2711 CrossRefGoogle Scholar
  2. 2.
    Ford-Perriss M, Abud H, Murphy M (2001) Fibroblast growth factors in the developing central nervous system. Clin Exp Pharmacol Physiol 28(7):493–503CrossRefPubMedGoogle Scholar
  3. 3.
    Mason I (2007) Initiation to end point: the multiple roles of fibroblast growth factors in neural development. Nat Rev Neurosci 8(8):583–596. doi:10.1038/nrn2189 CrossRefPubMedGoogle Scholar
  4. 4.
    Terwisscha van Scheltinga AF, Bakker SC, Kahn RS, Kas MJ (2013) Fibroblast growth factors in neurodevelopment and psychopathology. Neuroscientist 19(5):479–494. doi:10.1177/1073858412472399 CrossRefPubMedGoogle Scholar
  5. 5.
    Williams AJ, Yee P, Smith MC, Murphy GG, Umemori H (2016) Deletion of fibroblast growth factor 22 (FGF22) causes a depression-like phenotype in adult mice. Behav Brain Res 307:11–17. doi:10.1016/j.bbr.2016.03.047 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Eren-Kocak E, Turner CA, Watson SJ, Akil H (2011) Short-hairpin RNA silencing of endogenous fibroblast growth factor 2 in rat hippocampus increases anxiety behavior. Biol Psychiatry 69(6):534–540. doi:10.1016/j.biopsych.2010.11.020 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Brooks LR, Enix CL, Rich SC, Magno JA, Lowry CA, Tsai PS (2014) Fibroblast growth factor deficiencies impact anxiety-like behavior and the serotonergic system. Behav Brain Res 264:74–81. doi:10.1016/j.bbr.2014.01.053 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Scearce-Levie K, Roberson ED, Gerstein H, Cholfin JA, Mandiyan VS, Shah NM, Rubenstein JL, Mucke L (2008) Abnormal social behaviors in mice lacking Fgf17. Genes Brain Behav 7(3):344–354. doi:10.1111/j.1601-183X.2007.00357.x CrossRefPubMedGoogle Scholar
  9. 9.
    Terauchi A, Johnson-Venkatesh EM, Toth AB, Javed D, Sutton MA, Umemori H (2010) Distinct FGFs promote differentiation of excitatory and inhibitory synapses. Nature 465(7299):783–787. doi:10.1038/nature09041 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Evans SJ, Choudary PV, Neal CR, Li JZ, Vawter MP, Tomita H, Lopez JF, Thompson RC et al (2004) Dysregulation of the fibroblast growth factor system in major depression. Proc Natl Acad Sci U S A 101(43):15506–15511. doi:10.1073/pnas.0406788101 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Aurbach EL, Inui EG, Turner CA, Hagenauer MH, Prater KE, Li JZ, Absher D, Shah N et al (2015) Fibroblast growth factor 9 is a novel modulator of negative affect. Proc Natl Acad Sci U S A 112(38):11953–11958. doi:10.1073/pnas.1510456112 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Lin Y, Liu G, Wang F (2006) Generation of an Fgf9 conditional null allele. Genesis 44(3):150–154. doi:10.1002/gene.20194 CrossRefPubMedGoogle Scholar
  13. 13.
    Colvin JS, White AC, Pratt SJ, Ornitz DM (2001) Lung hypoplasia and neonatal death in Fgf9-null mice identify this gene as an essential regulator of lung mesenchyme. Development 128(11):2095–2106PubMedGoogle Scholar
  14. 14.
    Colvin JS, Green RP, Schmahl J, Capel B, Ornitz DM (2001) Male-to-female sex reversal in mice lacking fibroblast growth factor 9. Cell 104(6):875–889CrossRefPubMedGoogle Scholar
  15. 15.
    Murakami H, Okawa A, Yoshida H, Nishikawa S, Moriya H, Koseki H (2002) Elbow knee synostosis (Eks): a new mutation on mouse Chromosome 14. Mamm Genome 13(7):341–344. doi:10.1007/s00335-001-2143-6 CrossRefPubMedGoogle Scholar
  16. 16.
    Harada M, Murakami H, Okawa A, Okimoto N, Hiraoka S, Nakahara T, Akasaka R, Shiraishi Y et al (2009) FGF9 monomer-dimer equilibrium regulates extracellular matrix affinity and tissue diffusion. Nat Genet 41(3):289–298. doi:10.1038/ng.316 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Puk O, Moller G, Geerlof A, Krowiorz K, Ahmad N, Wagner S, Adamski J, de Angelis MH et al (2011) The pathologic effect of a novel neomorphic Fgf9(Y162C) allele is restricted to decreased vision and retarded lens growth. PLoS One 6(8):e23678. doi:10.1371/journal.pone.0023678 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Lum M, Turbic A, Mitrovic B, Turnley AM (2009) Fibroblast growth factor-9 inhibits astrocyte differentiation of adult mouse neural progenitor cells. J Neurosci Res 87(10):2201–2210. doi:10.1002/jnr.22047 CrossRefPubMedGoogle Scholar
  19. 19.
    Fuchs H, Gailus-Durner V, Adler T, Aguilar-Pimentel JA, Becker L, Calzada-Wack J, Da Silva-Buttkus P, Neff F et al (2011) Mouse phenotyping. Methods 53(2):120–135. doi:10.1016/j.ymeth.2010.08.006 CrossRefPubMedGoogle Scholar
  20. 20.
    Garrett L, Lie DC, de Angelis MH, Wurst W, Hölter SM (2012) Voluntary wheel running in mice increases the rate of neurogenesis without affecting anxiety-related behaviour in single tests. Bmc Neurosci 13Google Scholar
  21. 21.
    Hölter SM, Stromberg M, Kovalenko M, Garrett L, Glasl L, Lopez E, Guide J, Gotz A et al (2013) A broad phenotypic screen identifies novel phenotypes driven by a single mutant allele in Huntington’s disease CAG knock-in mice. PLoS One 8(11)Google Scholar
  22. 22.
    Stribl C, Samara A, Trumbach D, Peis R, Neumann M, Fuchs H, Gailus-Durner V, Hrabe de Angelis M et al (2014) Mitochondrial dysfunction and decrease in body weight of a transgenic knock-in mouse model for TDP-43. J Biol Chem 289(15):10769–10784CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Zimprich A, Garrett L, Deussing JM, Wotjak CT, Fuchs H, Gailus-Durner V, de Angelis MH, Wurst W et al (2014) A robust and reliable non-invasive test for stress responsivity in mice. Front Behav Neurosci 8:125. doi:10.3389/fnbeh.2014.00125 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Fuchs H, Schughart K, Wolf E, Balling R, Hrabe de Angelis M (2000) Screening for dysmorphological abnormalities—a powerful tool to isolate new mouse mutants. Mamm Genome 11(7):528–530CrossRefPubMedGoogle Scholar
  25. 25.
    Gailus-Durner V, Fuchs H, Adler T, Aguilar Pimentel A, Becker L, Bolle I, Calzada-Wack J, Dalke C et al (2009) Systemic first-line phenotyping. Methods Mol Biol 530:463–509. doi:10.1007/978-1-59745-471-1_25 CrossRefPubMedGoogle Scholar
  26. 26.
    Haller F, Prehn C, Adamski J (2010) Quantification of steroids in human and mouse plasma using online solid phase extraction coupled to liquid chromatography tandem mass spectrometry. Nat Protoc. doi:10.1038/nprot.2010.1022
  27. 27.
    Rathkolb B, Hans W, Prehn C, Fuchs H, Gailus-Durner V, Aigner B, Adamski J, Wolf E et al (2013) Clinical chemistry and other laboratory tests on mouse plasma or serum. Curr Protoc Mouse Biol 3(2):69–100. doi:10.1002/9780470942390.mo130043 CrossRefPubMedGoogle Scholar
  28. 28.
    Garrett L, Zhang J, Zimprich A, Niedermeier KM, Fuchs H, Gailus-Durner V, Hrabe de Angelis M, Vogt Weisenhorn D et al (2015) Conditional reduction of adult born doublecortin-positive neurons reversibly impairs selective behaviors. Front Behav Neurosci 9:302. doi:10.3389/fnbeh.2015.00302 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Latchney SE, Rivera PD, Mao XW, Ferguson VL, Bateman TA, Stodieck LS, Nelson GA, Eisch AJ (2014) The effect of spaceflight on mouse olfactory bulb volume, neurogenesis, and cell death indicates the protective effect of novel environment. J Appl Physiol (1985) 116(12):1593–1604. doi:10.1152/japplphysiol.01174.2013 CrossRefPubMedCentralGoogle Scholar
  30. 30.
    Paxinos G, Franklin K (2001) The mouse brain in stereotaxic coordinates. Academic Press, San DiegoGoogle Scholar
  31. 31.
    Team RDC (2011) R: a language and environment for statistical computing. Vienna, Austria : the R Foundation for Statistical Computing http://www.R-project.org/
  32. 32.
    Todo T, Kondo T, Nakamura S, Kirino T, Kurokawa T, Ikeda K (1998) Neuronal localization of fibroblast growth factor-9 immunoreactivity in human and rat brain. Brain Res 783(2):179–187CrossRefPubMedGoogle Scholar
  33. 33.
    Couillard-Despres S, Winner B, Schaubeck S, Aigner R, Vroemen M, Weidner N, Bogdahn U, Winkler J et al (2005) Doublecortin expression levels in adult brain reflect neurogenesis. Eur J Neurosci 21(1):1–14. doi:10.1111/j.1460–9568.2004.03813.x CrossRefPubMedGoogle Scholar
  34. 34.
    Robinson L, Plano A, Cobb S, Riedel G (2013) Long-term home cage activity scans reveal lowered exploratory behaviour in symptomatic female Rett mice. Behav Brain Res 250:148–156. doi:10.1016/j.bbr.2013.04.041 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Brown SD, Moore MW (2012) The International Mouse Phenotyping Consortium: past and future perspectives on mouse phenotyping. Mamm Genome 23(9–10):632–640. doi:10.1007/s00335-012-9427-x CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Mrosovsky N, Hampton RR (1997) Spatial responses to light in mice with severe retinal degeneration. Neurosci Lett 222(3):204–206CrossRefPubMedGoogle Scholar
  37. 37.
    Powell K, Ethun K, Taylor DK (2016) The effect of light level, CO2 flow rate, and anesthesia on the stress response of mice during CO2 euthanasia. Lab Anim 45(10):386–395. doi:10.1038/laban.1117 CrossRefGoogle Scholar
  38. 38.
    Swerdlow NR, Geyer MA, Braff DL (2001) Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges. Psychopharmacology 156(2–3):194–215CrossRefPubMedGoogle Scholar
  39. 39.
    Rasmussen DD, Crites NJ, Burke BL (2008) Acoustic startle amplitude predicts vulnerability to develop post-traumatic stress hyper-responsivity and associated plasma corticosterone changes in rats. Psychoneuroendocrinology 33(3):282–291. doi:10.1016/j.psyneuen.2007.11.010 CrossRefPubMedGoogle Scholar
  40. 40.
    Glenn DE, Acheson DT, Geyer MA, Nievergelt CM, Baker DG, Risbrough VB, Team MRS (2016) High and low threshold for startle reactivity associated with Ptsd symptoms but not Ptsd risk: evidence from a prospective study of active duty marines. Depress Anxiety 33(3):192–202. doi:10.1002/da.22475 CrossRefPubMedGoogle Scholar
  41. 41.
    Russo AS, Parsons RG (2017) Acoustic startle response in rats predicts inter-individual variation in fear extinction. Neurobiol Learn Mem 139:157–164. doi:10.1016/j.nlm.2017.01.008 CrossRefPubMedGoogle Scholar
  42. 42.
    Pineles SL, Blumenthal TD, Curreri AJ, Nillni YI, Putnam KM, Resick PA, Rasmusson AM, Orr SP (2016) Prepulse inhibition deficits in women with PTSD. Psychophysiology 53(9):1377–1385. doi:10.1111/psyp.12679 CrossRefPubMedGoogle Scholar
  43. 43.
    Liberzon I, Abelson JL (2016) Context processing and the neurobiology of post-traumatic stress disorder. Neuron 92(1):14–30. doi:10.1016/j.neuron.2016.09.039 CrossRefPubMedGoogle Scholar
  44. 44.
    Powell SB, Weber M, Geyer MA (2012) Genetic models of sensorimotor gating: relevance to neuropsychiatric disorders. Curr Top Behav Neurosci 12:251–318. doi:10.1007/7854_2011_195 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Risbrough V (2010) Behavioral correlates of anxiety. Curr Top Behav Neurosci 2:205–228CrossRefPubMedGoogle Scholar
  46. 46.
    Lledo PM, Alonso M, Grubb MS (2006) Adult neurogenesis and functional plasticity in neuronal circuits. Nat Rev Neurosci 7:179–193. doi:10.1038/nrn1867 CrossRefPubMedGoogle Scholar
  47. 47.
    Braun SM, Jessberger S (2014) Adult neurogenesis and its role in neuropsychiatric disease, brain repair and normal brain function. Neuropathol Appl Neurobiol 40:3–12. doi:10.1111/nan.12107 CrossRefPubMedGoogle Scholar
  48. 48.
    Bielsky IF and Young LJ (2004) Oxytocin, vasopressin, and social recognition in mammals. Peptides 25:1565–1574Google Scholar
  49. 49.
    Hoertnagl CM, Hofer A (2014) Social cognition in serious mental illness. Curr Opin Psychiatry 27:197–202CrossRefPubMedGoogle Scholar
  50. 50.
    Woodbury ME, Ikezu T (2014) Fibroblast growth factor-2 signaling in neurogenesis and neurodegeneration. J NeuroImmune Pharmacol 9(2):92–101. doi:10.1007/s11481-013-9501-5 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Lillian Garrett
    • 1
    • 2
  • Lore Becker
    • 2
    • 3
  • Jan Rozman
    • 2
    • 3
    • 4
  • Oliver Puk
    • 1
    • 2
    • 5
  • Tobias Stoeger
    • 2
    • 6
  • Ali Önder Yildirim
    • 2
    • 6
  • Alexander Bohla
    • 2
    • 6
    • 7
  • Oliver Eickelberg
    • 2
    • 6
  • Wolfgang Hans
    • 2
    • 3
  • Cornelia Prehn
    • 2
    • 3
  • Jerzy Adamski
    • 3
    • 8
  • Thomas Klopstock
    • 9
    • 10
    • 11
  • Ildikó Rácz
    • 12
  • Andreas Zimmer
    • 12
  • Martin Klingenspor
    • 13
  • Helmut Fuchs
    • 2
    • 3
  • Valerie Gailus-Durner
    • 2
    • 3
  • Wolfgang Wurst
    • 1
    • 10
    • 11
    • 14
  • Martin Hrabě de Angelis
    • 2
    • 3
    • 4
    • 8
  • Jochen Graw
    • 1
    • 2
  • Sabine M. Hölter
    • 1
    • 2
  1. 1.Institutes of Developmental GeneticsHelmholtz Zentrum MünchenNeuherbergGermany
  2. 2.German Mouse ClinicHelmholtz Zentrum MünchenNeuherbergGermany
  3. 3.Experimental GeneticsHelmholtz Zentrum MünchenNeuherbergGermany
  4. 4.German Center for Diabetes Research (DZD)NeuherbergGermany
  5. 5.CeGaT GmbHTübingenGermany
  6. 6.Comprehensive Pneumology Center, Institute of Lung Biology and Disease, Helmholtz Zentrum München, The German Center for Lung Research (DZL)German Research Center for Environmental HealthNeuherbergGermany
  7. 7.Satorius Stedim BiotechAubagneFrance
  8. 8.Experimental Genetics, Faculty of Life and Food Sciences WeihenstephanTechnische Universität München, Freising-WeihenstephanMunichGermany
  9. 9.Department of Neurology, Friedrich-Baur InstituteKlinikum der Ludwig-Maximilians-Universität MünchenMunichGermany
  10. 10.Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE)MunichGermany
  11. 11.Munich Cluster for Systems Neurology (SyNergy), Adolf-Butenandt-InstitutLudwig-Maximilians-Universität MünchenMunichGermany
  12. 12.Institute of Molecular Psychiatry, Medical FacultyUniversität BonnBonnGermany
  13. 13.Molecular Nutritional Medicine, Faculty of Life and Food Sciences WeihenstephanTechnische Universität MünchenMunichGermany
  14. 14.Developmental Genetics, Faculty of Life and Food Sciences WeihenstephanTechnische Universität München, Freising-WeihenstephanMunichGermany

Personalised recommendations