Doheny Eye Institute, University of California, Los Angeles, California 91103.
Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095.
J Neurosci. 2023 Mar 29;43(13):2291-2304. doi: 10.1523/JNEUROSCI.1723-22.2023. Epub 2023 Feb 24.
Increasing spike rates drive greater neuronal energy demand. In turn, mitochondrial ATP production leads to the generation of reactive oxygen species (ROS) that can modulate ion channel gating. Does ROS production autoregulate the excitability of a neuron? We investigated the links between retinal ganglion cell (RGC) excitability and spike activity-driven ROS production in male and female mice. Changes to the light-evoked and current-evoked spike patterns of functionally identified αRGC subtypes, along with their Na channel-gating properties, were recorded during experimentally induced decreases and increases of intracellular ROS. During periods of highest spike rates (e.g., following light onset in ON sustained RGCs and light offset in OFF sustained RGCs), these αRGC subtypes responded to reductions of ROS (induced by catalase or glutathione monoethyl ester) with higher spike rates. Increases in ROS (induced by mercaptosuccinate, antimycin-A, or HO) lowered spike rates. In ON and OFF transient RGCs, there were no changes in spike rate during ROS decreases but increased ROS increased spiking. This suggests that endogenous ROS are intrinsic neuromodulators in RGCs having high metabolic demands but not in RGCs with lower energy needs. We identified ROS-induced shifts in the voltage-dependent gating of specific isoforms of Na channels that account for the modulation of ON and OFF sustained RGC spike frequency by ROS-mediated feedback. ROS-induced changes to Na channel gating, affecting activation and inactivation kinetics, are consistent with the differing spike pattern alterations observed in RGC subtypes. Cell-autonomous generation of ROS during spiking contributes to tuning the spike patterns of RGCs. Energy production within retinal ganglion cells (RGCs) is accompanied by metabolic by-products harmful to cellular function. How these by-products modulate the excitability of RGCs bears heavily on visual function and the etiology of optic neuropathies. A novel hypothesis of how RGC metabolism can produce automodulation of electrical signaling was tested by identifying the characteristics and biophysical origins of changes to the excitability of RGCs caused by oxidizing by-products in the retina. This impacts our understanding of the pathophysiology of RGC dysfunction, supporting an emerging model in which increases in oxidizing chemical species during energy production, but not necessarily bioenergetic failure, lead to preferential degeneration of specific subtypes of RGCs, yielding loss of different aspects of visual capacity.
尖峰率的增加会导致神经元能量需求的增加。反过来，线粒体 ATP 的产生会导致活性氧物质 (ROS) 的产生，从而调节离子通道的门控。ROS 的产生是否会自我调节神经元的兴奋性？我们研究了雄性和雌性小鼠的视网膜神经节细胞 (RGC) 兴奋性与由尖峰活动驱动的 ROS 产生之间的联系。在实验诱导的细胞内 ROS 减少和增加期间，记录了功能鉴定的 αRGC 亚型的光诱发和电流诱发尖峰模式的变化，以及它们的钠通道门控特性。在尖峰率最高的时期（例如，在 ON 持续型 RGC 中的光起始后和 OFF 持续型 RGC 中的光结束后），这些 αRGC 亚型对 ROS 的减少（由过氧化氢酶或谷胱甘肽单乙酯诱导）有更高的尖峰率反应。ROS 的增加（由 mercaptosuccinate、antimycin-A 或 HO 诱导）降低了尖峰率。在 ON 和 OFF 瞬态 RGC 中，ROS 减少期间尖峰率没有变化，但增加 ROS 会增加尖峰。这表明，内源性 ROS 是具有高代谢需求的 RGC 中的内在神经调节剂，但不是具有较低能量需求的 RGC 中的内在神经调节剂。我们确定了 ROS 诱导的特定钠通道同工型电压依赖性门控的变化，这些变化解释了 ROS 介导的反馈对 ON 和 OFF 持续型 RGC 尖峰频率的调制。ROS 诱导的钠通道门控变化，影响激活和失活动力学，与在 RGC 亚型中观察到的不同尖峰模式改变一致。尖峰期间细胞自主产生的 ROS 有助于调节 RGC 的尖峰模式。在视网膜神经节细胞 (RGC) 中产生能量伴随着对细胞功能有害的代谢副产物。这些副产物如何调节 RGC 的兴奋性对视觉功能和视神经病变的病因有很大影响。通过确定氧化副产物对视网膜中 RGC 兴奋性的影响的特征和生物物理起源，测试了 RGC 代谢如何产生电信号自动调节的新假设。这影响了我们对 RGC 功能障碍病理生理学的理解，支持了一种新兴模型，即在能量产生过程中增加氧化化学物质，而不一定是生物能量衰竭，会导致特定 RGC 亚型的优先退化，从而导致视觉能力的不同方面丧失。
