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Characterization of a microglia-specific humanized P2X7 receptor knock-out mouse line: Implications for translational psychoneuroimmunology

Published online by Cambridge University Press:  01 September 2022

L. Urbina Trevino ,
I.-A. Von Mücke-Heim  and
J. Deussing
L. Urbina Trevino
Affiliation:
Max-Planck-Institute of Psychiatry, Molecular Neurogenetics, Munich, Germany
I.-A. Von Mücke-Heim*
Affiliation:
Max-Planck-Institute of Psychiatry, Molecular Neurogenetics, Munich, Germany Max-Planck-Institute of Psychiatry, Translational Research In Psychiatry, Munich, Germany
J. Deussing
Affiliation:
Max-Planck-Institute of Psychiatry, Molecular Neurogenetics, Munich, Germany
*
*Corresponding author.

Abstract

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Introduction

Depression is a common psychiatric disorder and chronic stress is considered its main environmental risk factor. Recently, immune processes including adenosine triphosphate mediated P2X7 receptor (P2X7R) signalling via microglia and macrophages (M/Ms) were found to play a critical role in depression genesis, by linking environmental stress to depression biology and symptoms.

Objectives

To characterize the role of human P2X7R (hP2X7R) in psychosocial and immune stress conditions, both in vitro and in vivo.

Methods

Several, custom designed mouse lines expressing the loxP-flanked, hP2X7R-sequence in the murine P2X7R locus were established. In addition, these mice possess a Cre-sensitive reporter and express a Cre recombinase fused to a mutant estrogen receptor ligand-binding domain in M/Ms. This enables conditional, tamoxifen-inducible hP2X7R inactivation and simultaneous tdTomato expression. First, we established primary microglia cell cultures and characterized them at baseline and following immune stimulation. Next, we performed behavioural assessment of hP2X7Rwt and microglia-specific hP2X7RKO mice following chronic psychosocial stress. Last, we developed a novel in vivo two-photon microscopy (TPM) approach by use of frontolimbic cranial windows.

Results

Primary hP2X7RKO microglia displayed significantly lower IL-1β production, increased survival and decreased morphological activation upon immune stimulation. Although hP2X7RKO mice showed a significant increase of locomotor activity at baseline, there was no impact on anxiety- and depressive-like phenotypes. Longitudinal in vivo TPM enabled morphometric characterization of cortical M/Ms over several weeks.

Conclusions

Our results illustrate the great potential of this humanized mouse line for translational psychiatry. In the future, this system could proof useful to evaluate immunomodulatory approaches in chronic stress and depression.

Disclosure

No significant relationships.

Keywords

Genetically engineered mouse models (GEMMs)chronic stress and depressionhuman P2X7 receptortranslational neuropsychiatry
Type
Abstract
Information
European Psychiatry , Volume 65 , Special Issue S1: Abstracts of the 30th European Congress of Psychiatry , June 2022 , pp. S368 - S367
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
Copyright
© The Author(s), 2022. Published by Cambridge University Press on behalf of the European Psychiatric Association
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