TY  - JOUR
AB  - 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.
AU  - von Mücke-Heim, I.A.*
AU  - Oldekamp, J.*
AU  - Metzger, M.W.*
AU  - Kläffgen, S.*
AU  - Tang, H.*
AU  - Walser, S.M.*
AU  - Dedic, N.*
AU  - Rammes, G.*
AU  - Holsboer, F.*
AU  - Wurst, W.
AU  - Deussing, J.M.*
C1  - 73574
C2  - 57099
CY  - Van Godewijckstraat 30, 3311 Gz Dordrecht, Netherlands
SP  - 1077-1092
TI  - Establishment and behavioural characterization of a novel constitutive P2X7 receptor knockout mouse line.
JO  - Purinergic Signal.
VL  - 21
IS  - 5
PB  - Springer
PY  - 2025
SN  - 1573-9538
ER  - 

TY  - JOUR
AB  - The purinergic P2X7 receptor (P2X7R) has attracted considerable interest as a potential target for various central nervous system (CNS) pathologies including affective and neurodegenerative disorders. To date, the distribution and cellular localization of the P2X7R in the brain are not fully resolved and a matter of debate mainly due to the limitations of existing tools. However, this knowledge should be a prerequisite for understanding the contribution of the P2X7R to brain disease. Here, we generated a genetic mouse model by humanizing the P2X7R in the mouse as mammalian model organism. We demonstrated its functionality and revealed species-specific characteristics of the humanized receptor, compared to the murine ortholog, regarding its receptivity to activation and modulation by 2′,3′-O-(benzoyl-4-benzoyl)-adenosine 5′-triphosphate (BzATP) and trifluoperazine (TFP). This humanized P2rx7 allele is accessible to spatially and temporally controlled Cre recombinase-mediated inactivation. In contrast to previously generated knockout (KO) mice, none of the described P2rx7 splice variants evade this null allele. By selective disruption and assessment of human P2RX7 expression in different brain regions and cell types, we were able to demonstrate that the P2X7R is specifically expressed in glutamatergic pyramidal neurons of the hippocampus. Also, P2X7R is expressed in major non-neuronal lineages throughout the brain, i.e., astrocytes, oligodendrocytes, and microglia. In conclusion, this humanized mouse model provides the means for detailed assessment of human P2X7R function in vivo including evaluation of agonists or antagonists. In addition, this conditional allele will enable future loss-of-function studies in conjunction with mouse models for CNS disorders.
AU  - Metzger, M.W.*
AU  - Walser, S.M.*
AU  - Aprile-Garcia, F.*
AU  - Dedic, N.*
AU  - Chen, A.
AU  - Holsboer, F.*
AU  - Arzt, E.*
AU  - Wurst, W.
AU  - Deussing, J.M.*
C1  - 50027
C2  - 41982
SP  - 153–170
TI  - Genetically dissecting P2rx7 expression within the central nervous system using conditional humanized mice.
JO  - Purinergic Signal.
VL  - 13
IS  - 2
PY  - 2017
SN  - 1573-9538
ER  - 

TY  - JOUR
AU  - Aprile-Garcia, F.*
AU  - Metzger, M.W.*
AU  - Dedic, N.*
AU  - Walser, S.M.*
AU  - Jakubcakova, V.*
AU  - Czamara, D.*
AU  - Mitkovski, M.*
AU  - Müller-Myhsok, B.*
AU  - Kimura, M.*
AU  - Wurst, W.
AU  - Stuehmer, W.*
AU  - Holsboer, F.*
AU  - Arzt, E.*
AU  - Deussing, J.M.*
C1  - 43663
C2  - 36722
CY  - Dordrecht
SP  - 718
TI  - P2RX7-a susceptibility gene for mood disorders?
JO  - Purinergic Signal.
VL  - 10
IS  - 4
PB  - Springer
PY  - 2014
SN  - 1573-9538
ER  -