ausblenden:
Schlagwörter:
P2X7 receptor, P2rx7 gene, pore formation, mouse model, knockout, gene expression
Zusammenfassung:
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.
