P2X7R modulation of visually evoked synaptic responses in the retina

Abstract

P2X7Rs are distributed throughout all layers of the retina, and thus, their localisation on various cell types puts into question their specific site(s) of action. Using a dark-adapted, ex vivo mouse retinal whole mount preparation, the present study aimed to characterise the effect of P2X7R activation on light-evoked, excitatory RGC ON-field excitatory post-synaptic potentials (fEPSPs) and on outer retinal electroretinogram (ERG) responses under comparable conditions. The pharmacologically isolated NMDA receptor-mediated RGC ON-fEPSP was reduced in the presence of BzATP, an effect which was significantly attenuated by A438079 and other selective P2X7R antagonists A804598 or AF27139. In physiological Krebs medium, BzATP induced a significant potentiation of the ERG a-wave, with a concomitant reduction in the b-wave and the power of the oscillatory potentials. Conversely, in the pharmacologically modified Mg2+-free perfusate, BzATP reduced both the a-wave and b-wave. The effects of BzATP on the ERG components were suppressed by A438079. A role for P2X7R function in visual processing in both the inner and outer retina under physiological conditions remains controversial. The ON-fEPSP was significantly reduced in the presence of A804598 but not by A438079 or AF27139. Furthermore, A438079 did not have any effect on the ERG components in physiological Krebs but potentiated and reduced the a-wave and b-wave, respectively, when applied to the pharmacologically modified medium. Therefore, activation of P2X7Rs affects the function in the retinal ON pathway. The presence of a high concentration of extracellular ATP would most likely contribute to the modulation of visual transmission in the retina in the pathophysiological microenvironment.

Purinergic modulation of frog electroretinographic responses: The role of the ionotropic receptor P2X7

“…The decrease of the amplitude of photoreceptor components—the ERG a-wave and the pharmacologically isolated mass receptor potential obtained by us during the P2X 7 R blockade—indicates that endogenous ATP, through its P2X 7 Rs, exerts a stimulating influence on the photoreceptor response. Our results are consistent with those of Puthussery et al (2006) and Chavda et al (2016), showing a potentiation of the ERG photoreceptor response under the influence of the selective P2X 7 R agonist Bz-ATP.…”

“…The contribution of the P2X 7 Rs to the flash ERG responses has been evaluated by investigating the effects of the selective P2X 7 R agonist Bz-ATP (rat and marmoset: Puthussery et al, 2006; mouse: Chavda et al, 2016). In these studies, the agonist treatment produced a potentiation of the ERG photoreceptor components (a-wave, modeled P III component) but an amplitude reduction of the postreceptoral components (b-wave, rod and cone P II components).…”

“…However, in the mutant mice, the amplitude of both the ERG b-wave (P II component) and the OP was greater and the ERG responses were faster as compared to the wild-type mice. In only one investigation (Chavda et al, 2016) were the effects of a selective P2X 7 R antagonist tested. The authors demonstrated that the selective P2X 7 R antagonist A438079, applied in a concentration of 10 µ M, had no effect on the a- and b-waves of the flash ERG, although it did reduce the effects of co-applied Bz-ATP.…”

Targeting the P2X7 Receptor in Age-Related Macular Degeneration

“…In the rodent retina, the P2XR is widely expressed in both inner and outer retina. Retinal ganglion cells, amacrine cells, horizontal cells, microglia and photoreceptors all express P2X7R or functional P2X7R [22,23,24,25].…”

P2X7 Receptor Antagonist A804598 Inhibits Inflammation in Brain and Liver in C57BL/6J Mice Exposed to Chronic Ethanol and High Fat Diet

“…Among the number of commercially available antagonists, we selected to use A804598 in these experiments due to its high potency and selectivity towards P2X7Rs from different species with the resultant block of agonist-stimulated release of IL-1β (Donnelly-Roberts et al 2009) and ability to readily cross the blood-brain barrier (Able et al 2011). This antagonist has been tested on neuroimmune signaling and behavioral consequences in vivo in experimental animal models of stress (Catanzaro et al 2014), neuropathic pain (Jung et al 2017), traumatic brain injury (Liu et al 2017), and visual processing in retina (Chavda et al 2016). We tested the effect of A804598 on the inflammatory responses in the brain and liver caused by exposure to chronic alcohol and high fat diet.…”