Department of Physiology, Northwestern University, Feinberg School of Medicine, Chicago 60611, IL.
Department of Physical Medicine and Rehabilitation, Northwestern University, Feinberg School of Medicine, Chicago 60611, IL.
eNeuro. 2021 Mar 22;8(2). doi: 10.1523/ENEURO.0378-20.2021. Print 2021 Mar-Apr.
Although amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease, motoneuron electrical properties are already altered during embryonic development. Motoneurons must therefore exhibit a remarkable capacity for homeostatic regulation to maintain a normal motor output for most of the life of the patient. In the present article, we demonstrate how maintaining homeostasis could come at a very high cost. We studied the excitability of spinal motoneurons from young adult SOD1(G93A) mice to end-stage. Initially, homeostasis is highly successful in maintaining their overall excitability. This initial success, however, is achieved by pushing some cells far above the normal range of passive and active conductances. As the disease progresses, both passive and active conductances shrink below normal values in the surviving cells. This shrinkage may thus promote survival, implying the previously large values contribute to degeneration. These results support the hypothesis that motoneuronal homeostasis may be "hypervigilant" in ALS and a source of accumulating stress.
虽然肌萎缩侧索硬化症（ALS）是一种成年发病的神经退行性疾病，但运动神经元的电特性在胚胎发育过程中已经发生改变。因此，运动神经元必须表现出非凡的自身稳态调节能力，以维持患者一生中的大部分正常运动输出。在本文中，我们展示了维持自身稳态可能会付出很高的代价。我们研究了从小鼠 SOD1(G93A)的年轻成年期到疾病晚期的脊髓运动神经元的兴奋性。最初，自身稳态非常成功地维持了它们的整体兴奋性。然而，这种最初的成功是通过将一些细胞推到远高于正常被动和主动电导范围来实现的。随着疾病的进展，存活细胞中的被动和主动电导都收缩到低于正常水平。这种收缩可能因此促进了存活，这意味着之前的大值会导致退化。这些结果支持这样一种假设，即运动神经元自身稳态在 ALS 中可能是“过度警惕”的，是累积应激的一个来源。
