P2X7 Receptor Modulation of Visual Responses in the Retina

Adenosine 5’ triphosphate (ATP)-gated P2X7 receptors (P2X7Rs) are known to act as conduits for photoreceptor and retinal ganglion cell (RGC) damage, consequences of various neurodegenerative conditions within the visual pathway. Growing evidence supports the notion that P2X7Rs and associated inflammatory mediators may coordinate microglia, the resident immune cells of the central nervous system (CNS), to play a genuine role in modulating neurotransmission. This study aimed to characterise the role of P2X7Rs in modulating outer and inner retinal function within the rod-mediated pathway, and in the putative microglial-mediated modulation of signal transmission in the retina. Excitatory components of outer and inner retinal function were assessed by recording light-evoked, extracellular transretinal electroretinogram (ERG), and ON and OFF retinal ganglion cell (RGC) field excitatory postsynaptic potential (fEPSP) responses from the acutely isolated, dark-adapted, mouse retina. Alterations to microglial morphology, under similar conditions, were also explored. Initial experiments confirmed the excitatory responses as predominantly mediated via the ‘classic’ rod photoreceptor – rod-ON bipolar cell – AII amacrine cell pathway. With the use of selective P2X7R antagonists, it was shown that P2X7R activation directly modulated photoreceptor, ON bipolar cell and ON RGC function, but not OFF RGC function, through partially independent mechanisms. A novel finding of this study demonstrated that acute application of the microglia-activating bacterial component, lipopolysaccharide (LPS) modulated inner retinal function, possibly through a P2X7R- and Pannexin-1-associated mechanism of microglial ATP release. These results were supported by observations of early morphometric changes to microglia caused by P2X7R activation and LPS, as revealed by immunofluorescence labelling and confocal laser scanning microscopy. Since changes in neurotransmission and microglial function are early indicators of neuropathology, these results contribute to the understanding of early neural-immune interactions in retinal disease, and in the central nervous system as a whole