부산대학교 도서관

• Atrx inactivation in the retina induces functional defects and amacrine cell death. • Timing of amacrine cell loss in Atrx-null retinas coincides with sensory input. • Light deprivation by dark rearing limits the extent of retinal dysfunction. • Blockage of light signaling through the ON pathway reduced amacrine cell loss. • Atrx exhibits activity-dependent functions in post-mitotic neurons in vivo. Mutation of the α-thalassemia/mental retardation syndrome X-linked protein, ATRX, causes intellectual disability and is associated with pleiotropic defects including ophthalmological abnormalities. We have previously demonstrated that Atrx deficiency in the mouse retina leads to the selective loss of inhibitory interneurons and inner retinal dysfunction. Onset of the amacrine cell neurodegenerative phenotype in Atrx-deficient retinas occurs postnatally after neuronal specification, and coincides with eye opening. Given this timing, we sought to interrogate the influence of light-dependent visual signaling on Atrx-mediated neuronal survival and function in the mouse retina. Retina-specific Atrx conditional knockout (cKO) mice were subjected to light deprivation using two different paradigms: (1) a dark-rearing regime, and (2) genetic deficiency of metabotropic glutamate receptor 6 (mGluR6) to block the ON retinal signaling pathway. Scotopic electroretinography was performed for adult dark-reared Atrx cKO mice and controls to measure retinal neuron function in vivo. Retinal immunohistochemistry and enumeration of amacrine cells were performed for both light deprivation paradigms. We observed milder normalized a-wave, b-wave and oscillatory potential (OP) deficits in electroretinograms of dark-reared Atrx cKO mice compared to light-exposed counterparts. In addition, amacrine cell loss was partially limited by genetic restriction of retinal signaling through the ON pathway. Our results suggest that the temporal features of the Atrx cKO phenotype are likely due to a combined effect of light exposure upon eye opening and coincident developmental processes impacting the retinal circuitry. In addition, this study reveals a novel activity-dependent role for Atrx in mediating post-replicative neuronal integrity in the CNS. [ABSTRACT FROM AUTHOR]