Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island.
George and Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, Rhode Island.
J Neurophysiol. 2019 Oct 1;122(4):1297-1311. doi: 10.1152/jn.00652.2018. Epub 2019 Jul 31.
Spinal motoneuron dysfunction and loss are pathological hallmarks of the neuromuscular disease spinal muscular atrophy (SMA). Changes in motoneuron physiological function precede cell death, but how these alterations vary with disease severity and motoneuron maturational state is unknown. To address this question, we assessed the electrophysiology and morphology of spinal motoneurons of presymptomatic mice older than 1 wk of age and tracked the timing of motor unit loss in this model using motor unit number estimation (MUNE). In contrast to other commonly used SMA mouse models, mice exhibit more typical postnatal development until postnatal day (P)11 or 12 and have longer survival (~3 wk of age). We demonstrate that motoneuron hyperexcitability, marked by hyperpolarization of the threshold voltage for action potential firing, was present at P9-10 and preceded the loss of motor units. Using MUNE studies, we determined that motor unit loss in this mouse model occurred 2 wk after birth. motoneurons were also larger in size, which may reflect compensatory changes taking place during postnatal development. This work suggests that motoneuron hyperexcitability, marked by a reduced threshold for action potential firing, is a pathological change preceding motoneuron loss that is common to multiple models of severe SMA with different motoneuron maturational states. Our results indicate voltage-gated sodium channel activity may be altered in the disease process. Changes in spinal motoneuron physiologic function precede cell death in spinal muscular atrophy (SMA), but how they vary with maturational state and disease severity remains unknown. This study characterized motoneuron and neuromuscular electrophysiology from the model of SMA. Motoneurons were hyperexcitable at postnatal day (P)9-10, and specific electrophysiological changes in motoneurons preceded functional motor unit loss at P14, as determined by motor unit number estimation studies.
脊髓运动神经元功能障碍和丧失是神经肌肉疾病脊髓性肌萎缩症 (SMA) 的病理标志。运动神经元生理功能的变化先于细胞死亡，但这些变化如何随疾病严重程度和运动神经元成熟状态而变化尚不清楚。为了解决这个问题，我们评估了年龄大于 1 周龄的 小鼠的脊髓运动神经元的电生理学和形态，并使用运动单位数量估计 (MUNE) 跟踪该模型中运动单位丧失的时间。与其他常用的 SMA 小鼠模型相比， 小鼠在出生后第 11 或 12 天之前表现出更典型的发育，并且存活时间更长（~3 周龄）。我们证明，运动神经元超兴奋性，表现为动作电位触发的阈值电压超极化，在 P9-10 时存在，并先于运动单位丧失。通过 MUNE 研究，我们确定该小鼠模型中的运动单位丧失发生在出生后 2 周。 运动神经元的尺寸也更大，这可能反映了出生后发育过程中发生的代偿性变化。这项工作表明，运动神经元超兴奋性，表现为动作电位触发的阈值降低，是一种发生在运动神经元丧失之前的病理变化，这在具有不同运动神经元成熟状态的多种严重 SMA 模型中都很常见。我们的研究结果表明，电压门控钠通道活性可能在疾病过程中发生改变。在脊髓性肌萎缩症 (SMA) 中，脊髓运动神经元生理功能的变化先于细胞死亡，但它们如何随成熟状态和疾病严重程度而变化尚不清楚。本研究从 模型中对运动神经元和神经肌肉电生理学进行了描述。在出生后第 9-10 天，运动神经元表现出超兴奋性，并且通过运动单位数量估计研究确定，在 P14 时，运动神经元的特定电生理变化先于功能性运动单位丧失。
