Anatomy and Neuroscience - Research Publications
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ItemRod and Cone Pathway Signalling Is Altered in the P2X7 Receptor Knock Out Mouse(PUBLIC LIBRARY SCIENCE, 2012-01-10)The P2X7 receptor (P2X7-R) is expressed in the retina and brain and has been implicated in neurodegenerative diseases. However, whether it is expressed by neurons and plays a role as a neurotransmitter receptor has been the subject of controversy. In this study, we first show that the novel vesicular transporter for ATP, VNUT, is expressed in the retina, verifying the presence of the molecular machinery for ATP to act as neurotransmitter at P2X7-Rs. Secondly we show the presence of P2X7-R mRNA and protein in the retina and cortex and absence of the full length variant 1 of the receptor in the P2X7-R knock out (P2X7-KO) mouse. The role of the P2X7-R in neuronal function of the retina was assessed by comparing the electroretinogram response of P2X7-KO with WT mice. The rod photoreceptor response was found to be similar, while both rod and cone pathway post-photoreceptor responses were significantly larger in P2X7-KO mice. This suggests that activation of P2X7-Rs modulates output of second order retinal neurons. In line with this finding, P2X7-Rs were found in the outer plexiform layer and on inner retinal cell classes, including horizontal, amacrine and ganglion cells. The receptor co-localized with conventional synapses in the IPL and was expressed on amacrine cells post-synaptic to rod bipolar ribbon synapses. In view of the changes in visual function in the P2X7-KO mouse and the immunocytochemical location of the receptor in the normal retina, it is likely the P2X7-R provides excitatory input to photoreceptor terminals or to inhibitory cells that shape both the rod and cone pathway response.
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ItemAmyloid Precursor Protein Is Required for Normal Function of the Rod and Cone Pathways in the Mouse Retina(PUBLIC LIBRARY SCIENCE, 2012-01-18)Amyloid precursor protein (APP) is a transmembrane glycoprotein frequently studied for its role in Alzheimer's disease. Our recent study in APP knockout (KO) mice identified an important role for APP in modulating normal neuronal development in the retina. However the role APP plays in the adult retina and whether it is required for vision is unknown. In this study we evaluated the role of APP in retinal function and morphology comparing adult wildtype (WT) and APP-KO mice. APP was expressed on neuronal cells of the inner retina, including horizontal, cone bipolar, amacrine and ganglion cells in WT mice. The function of the retina was assessed using the electroretinogram and although the rod photoreceptor responses were similar in APP-KO and WT mice, the post-photoreceptor, inner retinal responses of both the rod and cone pathways were reduced in APP-KO mice. These changes in inner retinal function did not translate to a substantial change in visual acuity as assessed using the optokinetic response or to changes in the gross cellular structure of the retina. These findings indicate that APP is not required for basic visual function, but that it is involved in modulating inner retinal circuitry.
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ItemNo Preview AvailableElectronic restoration of vision in those with photoreceptor degenerations(WILEY, 2012-09)Complete loss of vision is one of the most feared sequelae of retinal disease. Currently, there are few if any treatment options available to patients that may slow or prevent blindness in diseases caused by photoreceptor loss, such as retinitis pigmentosa and age-related macular degeneration. Electronic restoration of vision has emerged over recent years as a safe and viable option for those who have lost substantial numbers of photoreceptors and who are severely vision impaired. Indeed, there has been a dramatic increase in our understanding of what is required to restore vision using an electronic retinal prosthesis. Recent reports show that for some patients, restoration of vision to the point of reading large letters is possible. In this review, we examine the types of implants currently under investigation and the results these devices have achieved clinically. We then consider a range of engineering and biological factors that may need to be considered to improve the visual performance of newer-generation devices. With added research, it is hoped that the level of vision achieved with newer generation devices will steadily improve, resulting in enhanced quality of life for those with severe vision impairment.
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ItemNo Preview AvailableCcl2/Cx3cr1 Knockout Mice Have Inner Retinal Dysfunction but Are Not an Accelerated Model of AMD(ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2012-11)PURPOSE: The chemokine, Ccl2, and the fractalkine receptor, Cx3cr1, have both been implicated in the pathogenesis of age related macular degeneration (AMD), with mice lacking both genes exhibiting features of AMD by 3 months of age. However, recent reports indicate that this ascribed phenotype is due to the presence of a retinal degeneration mutation (crb1(rd8/rd8), rd8) on the background strain. Our aim was to characterize the retinal effects of lack of Ccl2 and Cx3cr1 (Ccl2(-/-)/Cx3cr1(EGFP/EGFP), CDKO-mice), in mice without the rd8 mutation. METHODS: Nine-month-old, CDKO and wildtype C57blk6J mice were investigated for retinal fundus appearance and histology. The function of the rod and cone pathways was assessed using the ERG. RESULTS: The CDKO mice did not develop lesions in the retinal fundus, and the ultrastructure of Bruch's membrane and the RPE were similar to that of C57blk6J mice. From the ERG, there was no change in the amplitude of the rod photoreceptor response, or in the rod or cone post-photoreceptor b-wave. However, the rod and cone ERG oscillatory potentials were significantly reduced in the CDKO animals, a phenotype apparent in Cx3cr1(EGFP/EGFP)- but not Ccl2(-/-)-founder lines. This correlated with aberrant amacrine cell morphology in the CDKO mice. In addition, Müller cells were gliotic and microglial morphology subtly altered, indicative of retinal stress. CONCLUSIONS: These results suggest that in the absence of the rd8 mutation, the CDKO-mouse has a mild inner retinal phenotype characterized by altered amacrine cell function, but that it is not an accelerated model of AMD.