Optogenetic Stimulation of the Superior Colliculus Confers Retinal Neuroprotection in a Mouse Glaucoma Model
Optogenetic Stimulation of the Superior Colliculus Confers Retinal Neuroprotection in a Mouse Glaucoma Model
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DOI：
10.1523/jneurosci.0872-18.2018
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发表时间：
2019-03-20
影响因子：
5.3
通讯作者：
Moons, Lieve
中科院分区：
文献类型：
--
作者：
Geeraerts, Emiel;Claes, Marie;Moons, Lieve
青光眼的特征在于眼睛中视网膜神经节细胞（RGC）的进行性损失，其最终导致视觉损害甚至失明。由于目前的治疗通常无法阻止疾病进展，因此需要新的神经保护疗法来支持RGC存活。各种研究表明，大脑中的视觉目标中心支持RGC的功能和生存。在这里，我们探讨了是否增加这些投射区之一的神经元活动可以提高小鼠青光眼模型中RGCs的存活率。通过一种新的光遗传学刺激范例建立了重要的鼠RGC靶区域上级丘（SC）的延长激活。通过利用稳定的阶跃功能视蛋白（SSFO）的独特通道动力学，仅用短暂的光脉冲实现SC的延长刺激。SSFO介导的丘刺激证实了免疫组化的即时早期基因c-Fos和行为跟踪，这两个表现出一致的神经元活动后，反复刺激。最后，在青光眼模型的小鼠中研究了光遗传学丘刺激的神经保护潜力，发现RGC损失减少了63%。这项工作描述了光遗传学丘刺激的新范例，并首次证明增加靶神经元活性可以增加投射神经元的存活。
Glaucoma is characterized by a progressive loss of retinal ganglion cells (RGCs) in the eye, which ultimately results in visual impairment or even blindness. Because current therapies often fail to halt disease progression, there is an unmet need for novel neuroprotective therapies to support RGC survival. Various research lines suggest that visual target centers in the brain support RGC functioning and survival. Here, we explored whether increasing neuronal activity in one of these projection areas could improve survival of RGCs in a mouse glaucoma model. Prolonged activation of an important murine RGC target area, the superior colliculus (SC), was established via a novel optogenetic stimulation paradigm. By leveraging the unique channel kinetics of the stabilized step function opsin (SSFO), protracted stimulation of the SC was achieved with only a brief light pulse. SSFO-mediated collicular stimulation was confirmed by immunohistochemistry for the immediate-early gene c-Fos and behavioral tracking, which both demonstrated consistent neuronal activity upon repeated stimulation. Finally, the neuroprotective potential of optogenetic collicular stimulation was investigated in mice of either sex subjected to a glaucoma model and a 63% reduction in RGC loss was found. This work describes a new paradigm for optogenetic collicular stimulation and a first demonstration that increasing target neuron activity can increase survival of the projecting neurons.