P2X7 Receptor-Related Genetic Mouse Models – Tools for Translational Research in Psychiatry

Abstract

Depression is a common psychiatric disorder and the leading cause of disability worldwide. Although treatments are available, only about 60% of treated patients experience a significant improvement in disease symptoms. Numerous clinical and rodent studies have identified the purinergic P2X7 receptor (P2X7R) as one of the genetic factors potentially contributing to the disease risk. In this respect, genetically engineered mouse models targeting the P2X7R have become increasingly important in studying designated immunological features and subtypes of depression in vivo. This review provides an overview of the P2X7R -related mouse lines currently available for translational psychiatric research and discusses their strengths, weaknesses, and potentials.

Variation along P2RX7 interacts with early traumas on severity of anxiety suggesting a role for neuroinflammation

“…In addition, P2X7R directly regulates hippocampal glutamate release and influences the signalling pathway of brain-derived neurotrophic factor (BDNF), which’s impairment is a vulnerability factor for anxiety disorders 53 . The above mechanism has been proposed to play a role in the effect of chronic stress leading to impaired neuroplasticity and the appearance of depressive-like behaviour, while blockade of the P2RX7- NLRP3-IL1β pathway may promote stress resilience via the involvement of microglia and monocytes 54 , thus supporting the possible role of P2X7R signalling as a connecting point between chronic stress and clinical mood symptoms 55 , 56 . As we mentioned before, only a very few studies, and usually not primarily focusing on anxiety, have reported results on the potential role of the P2RX7 gene in anxiety, and none of them considered the possible interacting role of stress, although in one previous study rs208294 was found to be associated with mood disorder outcomes in a relationship mediated by neuroticism, a personality trait which is associated with less adaptive responses and increased anxiety upon exposure to stress 24 .…”

The human P2X7 receptor alters microglial morphology and cytokine secretion following immunomodulation

“…This is highly important, since P2X7R has been hypothesized to mediate psychosocial stress induced neuroinflammation and ultimately depression and depressive-like behaviours, respectively (von Mücke-Heim and von Muecke-Heim et al, 2021). Accordingly, clinical trials have demonstrated the effect of gain-of-function single nucleotide polymorphisms (SNPs) on depression (Andrejew et al, 2020;Ribeiro et al, 2019a;Urbina-Treviño et al, 2022;von Mücke-Heim and Deussing, 2022), which fits the hypothesis of an increased immune activation along with defective inflammation resolution mechanisms in depression (Debnath et al, 2021). Our cytokine findings are furthermore in line with the well-known connection between toll-like receptor mediated LPS effects in pro-IL-1β production and P2X7R induced caspase-1 activation in amplifying mature IL-1β release (Ferrari et al, 2006;Mingam et al, 2008).…”

Embers of the Past: Early Childhood Traumas Interact with Variation in P2RX7 Gene Implicated in Neuroinflammation on Markers of Current Suicide Risk

“…This leads to the activation of the NRLP3-associated inflammasome, which in turn eventuates the enhanced release of proinflammatory cytokines IL-1β and IL-18, while P2X7R activation also facilitate the release of other cytokines, such as IL-6 and TNF-α [90]. The above process has been suggested to play a significant role in the impact of chronic stress, leading to impaired neuroplasticity and the emergence of depressive-like behaviour, while pharmacological or genetic blockade of the P2RX7-NLRP3-IL1β pathway might foster resilience against stress via the involvement of microglia and monocytes, suggesting the potential role of P2X7R signalling as a connecting point between chronic stress and mood disorder [91,92].…”