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Crybb2 Mutations Consistently Affect Schizophrenia Endophenotypes in Mice

  • Tamara Heermann
  • Lillian Garrett
  • Wolfgang Wurst
  • Helmut Fuchs
  • Valerie Gailus-Durner
  • Martin Hrabě de Angelis
  • Jochen Graw
  • Sabine M. Hölter
Article

Abstract

As part of the βγ-superfamily, βB2-crystallin (CRYBB2) is an ocular structural protein in the lens, and mutation of the corresponding gene can cause cataracts. CRYBB2 also is expressed in non-lens tissue such as the adult mouse brain and is associated with neuropsychiatric disorders such as schizophrenia. Nevertheless, the robustness of this association as well as how CRYBB2 may contribute to disease-relevant phenotypes is unknown. To add further clarity to this issue, we performed a comprehensive analysis of behavioral and neurohistological alterations in mice with an allelic series of mutations in the C-terminal end of the Crybb2 gene. Behavioral phenotyping of these three βB2-mutant lines Crybb2O377, Crybb2Philly, and Crybb2Aey2 included assessment of exploratory activity and anxiety-related behavior in the open field, sensorimotor gating measured by prepulse inhibition (PPI) of the acoustic startle reflex, cognitive performance measured by social discrimination, and spontaneous alternation in the Y-maze. In each mutant line, we also quantified the number of parvalbumin-positive (PV+) GABAergic interneurons in selected brain regions that express CRYBB2. While there were allele-specific differences in individual behaviors and affected brain areas, all three mutant lines exhibited consistent alterations in PPI that paralleled alterations in the PV+ cell number in the thalamic reticular nucleus (TRN). The direction of the PPI change mirrored that of the TRN PV+ cell number thereby suggesting a role for TRN PV+ cell number in modulating PPI. Moreover, as both altered PPI and PV+ cell number are schizophrenia-associated endophenotypes, our result implicates mutated Crybb2 in the development of this neuropsychiatric disorder.

Keywords

Crybb2 Schizophrenia Parvalbumin Prepulse inhibition (PPI) Thalamic reticular nucleus (TRN) 

Abbreviations

ACC

anterior cingulate cortex

ASR

acoustic startle response

CA1-3

cornu ammonis area 1–3

βB2-crystallin

Crybb2

DAPI

4,6-diamidino-2-phenylindol

DG

dentate gyrus

OF

open field

PV+

parvalbumin-positive

PPI

prepulse inhibition

RSC

granular retrosplenial cortex

SD

social discrimination

TRN

thalamic reticular nucleus

QTL

quantitative trait loci

Notes

Acknowledgements

The authors thank Jan Einicke and Bettina Sperling as well as Erika Bürkle and Monika Stadler for expert technical assistance.

Authors’ Contributions

TH made contributions to conceptualization, methodology, formal analysis, writing (original draft), and visualization. LG made contributions to conceptualization, methodology, formal analysis, supervision, and writing (original draft). JG made contributions to conceptualization, resources, and writing (review and editing). VGD, HF, and MHdA contributed to conceptualization, methodology, and supervision of experiments at the German Mouse Clinic. WW and SMH contributed to conceptualization, resources, supervision, formal analysis, writing (original draft), and funding acquisition.

Funding

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 DFG grant ‘DJ-1 Linked Neurodegeneration Pathways in New Mouse Models of Parkinson’s Disease’ (WU 164/5-1) to WW.

Compliance with Ethical Standards

Ethics Approval and Consent to Participate

This animal work was approved ethically by the Regierung von Oberbayern in Germany.

Competing Interests

None.

Supplementary material

12035_2018_1365_MOESM1_ESM.docx (58 kb)
ESM 1 (DOCX 58 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Tamara Heermann
    • 1
    • 2
  • Lillian Garrett
    • 1
    • 3
  • Wolfgang Wurst
    • 1
    • 4
    • 5
    • 6
  • Helmut Fuchs
    • 3
  • Valerie Gailus-Durner
    • 3
  • Martin Hrabě de Angelis
    • 3
    • 7
    • 8
  • Jochen Graw
    • 1
  • Sabine M. Hölter
    • 1
    • 3
  1. 1.Institute of Developmental GeneticsHelmholtz Zentrum München, German Research Centre for Environmental HealthNeuherbergGermany
  2. 2.Max Planck Institute of BiochemistryMunichGermany
  3. 3.German Mouse Clinic, Institute of Experimental GeneticsHelmholtz Zentrum München, German Research Centre for Environmental HealthNeuherbergGermany
  4. 4.Developmental GeneticsTechnische Universität München- Weihenstephan, c/o Helmholtz Zentrum MünchenMunichGermany
  5. 5.German Centre of Neurodegenerative Diseases (DZNE)MunichGermany
  6. 6.Munich Cluster of Systems Neurology (SyNergy)Adolf-Butenandt-Institut, Ludwig-Maximilians-Universität MünchenMunichGermany
  7. 7.Experimental Genetics, School of Life Science WeihenstephanTechnische Universität MünchenFreisingGermany
  8. 8.German Center for Diabetes Research (DZD)NeuherbergGermany

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