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Pamela S Lagali, Hayam A Bassam, David J Picketts, Catherine Tsilfidis; Analysis of retinal ganglion cell and post-retinal phenotypes in Atrx-deficient mice. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1859.
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Mutations in the chromatin remodeling protein Atrx cause ATR-X Syndrome. Deficiency of Atrx in the mouse retina causes the selective loss of amacrine and horizontal cells and inner retinal dysfunction. It is unknown if these defects impact retinal output and subsequent processing or transmission of visual signals to the brain. We aim to analyze the retinal ganglion cell (RGC) phenotype and visual cortex activity in Atrx-deficient mice to gain insight into the scope of visual function mediated by Atrx-dependent chromatin remodeling and the extent of ocular and cortical deficits that may affect individuals with ATR-X Syndrome.
Conditional mouse genetic knockout approaches were used to selectively remove the Atrx chromatin remodeling factor from different retinal cell populations in vivo. Transgenic mice harbouring a mutation found in ATR-X Syndrome patients represent a model of disease-associated constitutive Atrx deficiency. Immunohistochemistry and fluorescence microscopy of Atrx-deficient retinal tissues was performed to evaluate and enumerate the RGC population. Retinal function was assessed by full-field flash and pattern electroretinography (ERG). Visual evoked potentials were measured to examine cortical responses to visual stimuli.
There were no significant reductions in the number of RGCs in any of the mouse models of Atrx deficiency compared to controls. RGC viability did not depend on intrinsic Atrx expression or on extrinsic Atrx expression in pre-synaptic retinal bipolar cells. However, pan-retinal knockout of Atrx resulted in a significant reduction in pattern ERG amplitudes, indicating RGC functional deficits. Furthermore, loss of Atrx in the retina resulted in dramatically reduced visual evoked potentials elicited from the visual cortex.
Atrx is not required for the survival of excitatory retinal neurons, including RGCs. However, excitatory visual neurotransmission through the inner retina and onto the visual cortex is compromised in the absence of Atrx. Therefore, Atrx-mediated chromatin remodeling plays a role in the proper function of retinal bipolar cells and RGCs that impacts the propagation of visual signals within the retina and onto higher visual centres. Our findings expand the range of visual deficits that may affect ATR-X Syndrome patients and suggest that cortical dysfunction caused by Atrx deficiency extends to visual processing centres of the brain.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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