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.

α-地中海贫血/智力迟钝综合征 X 连锁蛋白 ATRX 的突变导致智力障碍，并与包括眼科异常在内的多效性缺陷有关。我们之前已经证明，小鼠视网膜中的 Atrx 缺乏会导致抑制性中间神经元的选择性丧失和视网膜内功能障碍。Atrx 缺陷视网膜中无长突细胞神经退行性表型的发作发生在出生后神经元规范后，并且与睁眼同时发生。鉴于这个时机，我们试图探究光依赖视觉信号对 Atrx 介导的小鼠视网膜神经元存活和功能的影响。使用两种不同的范例对视网膜特异性 Atrx 条件性敲除 (cKO) 小鼠进行光照剥夺：(1) 暗饲养方案，(2) 代谢型谷氨酸受体 6 (mGluR6) 的遗传缺陷，无法阻断 ON 视网膜信号通路。对成年暗饲养 Atrx cKO 小鼠和对照组进行暗眼视网膜电图，以测量视网膜神经元功能在体内。对两种光剥夺范例进行视网膜免疫组织化学和无长突细胞计数。我们观察到与光照对应的小鼠相比，深色饲养的 Atrx cKO 小鼠的视网膜电图中较温和的标准化 a 波、b 波和振荡电位 (OP) 缺陷。此外，无长突细胞丢失部分受限于通过 ON 途径的视网膜信号传导的遗传限制。我们的研究结果表明，Atrx cKO 表型的时间特征可能是由于光照对眼睛张开的综合影响以及同时影响视网膜电路的发育过程。此外，这项研究揭示了 Atrx 在调节 CNS 复制后神经元完整性方面的新的活动依赖性作用。