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Kirstan Vessey, Andrew Jobling, Erica Fletcher; Absence of a functional P2X7 receptor slows photoreceptor degeneration in the rd1 mouse. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3267.
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Adenosine tri-phosphate (ATP) acts as a neurotransmitter by stimulating purinoceptors, which include the P2X ligand gated ion channels. Blockade of P2X receptors increases the survival of rod photoreceptors in the rd1 mouse model, through a mechanism likely to be mediated by the P2X7 subclass of receptors (P2X7-R). The aim of the current study was to investigate the role of the P2X7-R in mouse retinal degeneration.
The rd1 mouse line was crossed with a P2X7-R knock out mouse (P2X7-KO) to generate a P2X7-KO/rd1 mouse. Photoreceptor numbers were quantified and the inflammatory response was assessed by counting microglia in rd1 (n=6) and P2X7-KO/rd1 (n=6) mice at postnatal day 14 (P14) and P18. An Illumina Array was used to determine changes in gene expression between rd1 and P2X7-KO/rd1 mice at P14. Genes highlighted in the array associated with neuronal function and inflammatory pathways were investigated using quantitative RT-PCR.
Rd1 mice lacking the P2X7-R had 30% more photoreceptors than the control rd1 mice at P14 (p<0.01). In addition, there were 35% less microglia in the photoreceptor layer of P2X7-KO/rd1 mice (p<0.01) indicating a reduced inflammatory response in these mice. Results from the Illumina array were consistent with these morphological findings showing an increase in genes associated with photoreceptor function (Gnat1, Pde6a, Ctbp2, Pclo, Cacnb2) and second order neuronal function (Trpm1) in the P2X7-KO/rd1 mice. In line with this, there was enrichment for genes associated with reduced apoptosis (Birc1cl & Diablo). In addition, genes associated with attraction of monocytes (Ccl7 & 27; Cxcl16 &12), pro-inflammatory caspases (Casp1 & 4) and proinflammatory chemokines (Ccl 6, 9, 19, & 21) were reduced in the P2X7-KO/rd1 mice.
These results suggest blockade of the P2X7-R may be a useful therapy in slowing photoreceptor death in retinal degeneration. Inhibition of the P2X7-R may reduce photoreceptor death by blocking direct neurotoxicity mediated by extracellular ATP and indirect toxicity mediated by the inflammatory responses of microglia.
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