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Deficiency of the palmitoyl acyltransferase ZDHHC7 impacts brain and behavior of mice in a sex-specific manner

  • Christa HohoffEmail author
  • Mingyue Zhang
  • Oliver Ambrée
  • Mykola Kravchenko
  • Jens Buschert
  • Nicole Kerkenberg
  • Nataliya Gorinski
  • Dalia Abdel Galil
  • Christiane Schettler
  • Kari Lavinia vom Werth
  • Maximilian F.-J. Wewer
  • Ilona Schneider
  • Dominik Grotegerd
  • Lydia Wachsmuth
  • Cornelius Faber
  • Boris V. Skryabin
  • Juergen Brosius
  • Evgeni Ponimaskin
  • Weiqi ZhangEmail author
Original Article

Abstract

The palmitoyl acyltransferase ZDHHC7 belongs to the DHHC family responsible for the covalent attachment of palmitic acid (palmitoylation) to target proteins. Among synaptic proteins, its main targets are sex steroid receptors such as the estrogen receptors. When palmitoylated, these couple to membrane microdomains and elicit non-genomic rapid responses. Such coupling is found particularly in cortico-limbic brain areas which impact structure, function, and behavioral outcomes. Thus far, the functional role of ZDHHC7 has not been investigated in this context. To directly analyze an impact of ZDHHC7 on brain anatomy, microstructure, connectivity, function, and behavior, we generated a mutant mouse in which the Zdhhc7 gene is constitutively inactivated. Male and female Zdhhc7/ mice were phenotypically compared with wild-type mice using behavioral tests, electrophysiology, protein analyses, and neuroimaging with diffusion tensor-based fiber tractography. Zdhhc7-deficiency impaired excitatory transmission, synaptic plasticity at hippocampal Schaffer collateral CA1 synapses, and hippocampal structural connectivity in both sexes in similar manners. Effects on both sexes but in different manners appeared in medial prefrontal cortical synaptic transmission and in hippocampal microstructures. Finally, Zdhhc7-deficiency affected anxiety-related behaviors exclusively in females. Our data demonstrated the importance of Zdhhc7 for assembling proper brain structure, function, and behavior on a system level in mice in a sex-related manner. Given the prominent role of sex-specificity also in humans and associated mental disorders, Zdhhc7/ mice might provide a promising model for in-depth investigation of potentially underlying sex-specifically altered mechanisms.

Keywords

Palmitoylation Zdhhc7-deficiency Constitutive knockout mouse Small animal imaging Electrophysiological recordings Behavioral phenotyping 

Notes

Acknowledgements

The authors thank Kathrin Schwarte from the Department of Psychiatry and Psychotherapy and Florian Breuer from the Department of Clinical Radiology, both University of Münster, Germany, for their excellent technical help and Stephanie Klco-Brosius for editorial advice. The work was supported by the Otto Creutzfeldt Center for Cognitive and Behavioral Neuroscience of the University of Münster, the Interdisciplinary Centre for Clinical Research (IZKF) of the University of Münster Medical School (Zha3-005-14 and core unit PIX), and by the Deutsche Forschungsgemeinschaft (ZH 34/3-1 to W.Z.).

Funding

This study was funded by the Interdisciplinary Centre for Clinical Research (IZKF) of the University of Münster Medical School (Zha3-005-14 and core unit PIX) and by the Deutsche Forschungsgemeinschaft (ZH 34/3-1 to W.Z.). It was further supported by the Otto Creutzfeldt Center for Cognitive and Behavioral Neuroscience of the University of Münster.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest. No current external funding sources for this study had any role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Furthermore, the authors do not have any competing interests.

Research involving human and/or animal participants

The presented work was in accordance with all current regulations covering animal experimentation in Germany and the EU (European Communities Council Directive 2010/63/EU). All experiments were approved by the local authority and the “Animal Welfare Officer” of the University of Münster.

Informed consent

Informed consent was obtained from all authors included in the study.

Supplementary material

429_2019_1898_MOESM1_ESM.pdf (1.8 mb)
Supplementary material 1 (PDF 1875 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Christa Hohoff
    • 1
    Email author
  • Mingyue Zhang
    • 1
  • Oliver Ambrée
    • 1
    • 2
  • Mykola Kravchenko
    • 1
  • Jens Buschert
    • 1
    • 3
  • Nicole Kerkenberg
    • 1
    • 3
  • Nataliya Gorinski
    • 4
  • Dalia Abdel Galil
    • 4
  • Christiane Schettler
    • 1
  • Kari Lavinia vom Werth
    • 1
  • Maximilian F.-J. Wewer
    • 1
  • Ilona Schneider
    • 1
    • 3
  • Dominik Grotegerd
    • 1
  • Lydia Wachsmuth
    • 5
  • Cornelius Faber
    • 5
  • Boris V. Skryabin
    • 6
    • 7
  • Juergen Brosius
    • 7
    • 8
  • Evgeni Ponimaskin
    • 4
  • Weiqi Zhang
    • 1
    Email author
  1. 1.Department of Psychiatry and PsychotherapyUniversity of MünsterMunsterGermany
  2. 2.Department of Behavioral BiologyUniversity of OsnabrückOsnabrückGermany
  3. 3.Otto Creutzfeldt Center for Cognitive and Behavioral NeuroscienceUniversity of MünsterMunsterGermany
  4. 4.Cellular Neurophysiology, Center of PhysiologyHannover Medical SchoolHannoverGermany
  5. 5.Department of Clinical RadiologyUniversity of MünsterMunsterGermany
  6. 6.Department of Medicine, Core Facility Transgenic Animal and Genetic Engineering Models (TRAM)University of MünsterMunsterGermany
  7. 7.Institute of Experimental PathologyZMBE, University of MünsterMunsterGermany
  8. 8.Institutes for Systems GeneticsWest China Hospital, Sichuan UniversityChengduChina

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