Journal Article

DZNE-2025-01239

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Establishment and behavioural characterization of a novel constitutive P2X7 receptor knockout mouse line.

von Mücke-Heim, I.-A. ; Oldekamp, J. ; Metzger, M. W. ; Kläffgen, S. ; Tang, H. ; Walser, S. M. ; Dedic, N. ; Rammes, G. ; Holsboer, F. ; Wurst, W.DZNE* ; Deussing, J. M.

2025
Springer Science + Business Media B.V. Dordrecht

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Please use a persistent id in citations: doi:10.1007/s11302-025-10074-x

Abstract: The P2X7 receptor is an adenosine triphosphate (ATP)-gated ion channel expressed in different cell types of the brain. Polymorphisms in the P2RX7 gene have repeatedly been associated with psychiatric disorders including major depression. Depression is a stress-related disorder in which a dysregulation of the immune system has attracted increasing attention as a potential disease mechanism. The well-documented role of P2X7 in inflammatory conditions advocates its involvement in immune system dysregulation and depression genesis. However, understanding its exact role requires further research using appropriate animal models. Unfortunately, some of the most widely used P2X7 knockout mouse models are limited in their utility by the continuous expression of certain P2rx7 splice variants or even activation of de novo transcripts. To overcome this limitation, we generated a novel constitutive and complete P2X7 KO mouse line. These KO mice lack all known murine splice variants and protein expression resulting in a loss-of-function as confirmed by calcium imaging and by the inability of P2X7-deficient peritoneal macrophages to mount an appropriate interleukin (IL)-1β response. Comprehensive characterization using a battery of tests assessing locomotion, anxiety- and depression-related as well as social behaviour revealed differences in locomotor and exploratory behaviours. P2X7 KO mice showed slightly increased locomotor activity and reduced anxiety-related behaviour at baseline. Under conditions of chronic stress exposure, genotype-dependent differences largely dissolved while P2X7 deficiency promoted enhanced stress resilience with regard to social behaviour. Taken together, our findings add further evidence for an involvement of the P2X7 in shaping different behavioural responses and their modulation by stressful environments. This novel loss-of-function model will contribute to a better understanding of P2X7 in stress-associated behaviours in basic and translational neuropsychiatric research.

Keyword(s): Animals (MeSH) ; Receptors, Purinergic P2X7: genetics (MeSH) ; Receptors, Purinergic P2X7: metabolism (MeSH) ; Mice, Knockout (MeSH) ; Mice (MeSH) ; Behavior, Animal: physiology (MeSH) ; Male (MeSH) ; Mice, Inbred C57BL (MeSH) ; Depression: genetics (MeSH) ; Depression: metabolism (MeSH) ; Anxiety: genetics (MeSH) ; Anxiety: metabolism (MeSH) ; Disease Models, Animal (MeSH) ; Stress, Psychological: metabolism (MeSH) ; Behaviour ; Knockout mice ; P2X7 receptor ; P2rx7 gene ; Purinergic ; Receptors, Purinergic P2X7 ; P2rx7 protein, mouse

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Contributing Institute(s):

1. Genome Engineering (AG Wurst)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2025

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; DEAL Springer ; Essential Science Indicators ; IF < 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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