Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig 04103, Germany
Rudolf-Schönheimer Institute for Biochemistry, Leipzig University, Leipzig 04103, Germany.
J Neurosci. 2021 Jan 13;41(2):376-389. doi: 10.1523/JNEUROSCI.2142-20.2020. Epub 2020 Nov 20.
Dysfunction of neuronal circuits is an important determinant of neurodegenerative diseases. Synaptic dysfunction, death, and intrinsic activity of neurons are thought to contribute to the demise of normal behavior in the disease state. However, the interplay between these major pathogenic events during disease progression is poorly understood. Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by a deficiency in the ubiquitously expressed protein SMN and is characterized by motor neuron death, skeletal muscle atrophy, as well as dysfunction and loss of both central and peripheral excitatory synapses. These disease hallmarks result in an overall reduction of neuronal activity in the spinal sensory-motor circuit. Here, we show that increasing neuronal activity by chronic treatment with the FDA-approved potassium channel blocker 4-aminopyridine (4-AP) improves motor behavior in both sexes of a severe mouse model of SMA. 4-AP restores neurotransmission and number of proprioceptive synapses and neuromuscular junctions (NMJs), while having no effects on motor neuron death. In addition, 4-AP treatment with pharmacological inhibition of p53-dependent motor neuron death results in additive effects, leading to full correction of sensory-motor circuit pathology and enhanced phenotypic benefit in SMA mice. Our study reveals that 4-AP-induced increase of neuronal activity restores synaptic connectivity and function in the sensory-motor circuit to improve the SMA motor phenotype. Spinal muscular atrophy (SMA) is a neurodegenerative disease, characterized by synaptic loss, motor neuron death, and reduced neuronal activity in spinal sensory-motor circuits. However, whether these are parallel or dependent events is unclear. We show here that long-term increase of neuronal activity by the FDA-approved drug 4-aminopyridine (4-AP) rescues the number and function of central and peripheral synapses in a SMA mouse model, resulting in an improvement of the sensory-motor circuit and motor behavior. Combinatorial treatment of pharmacological inhibition of p53, which is responsible for motor neuron death and 4-AP, results in additive beneficial effects on the sensory-motor circuit in SMA. Thus, neuronal activity restores synaptic connections and improves significantly the severe SMA phenotype.
神经元回路功能障碍是神经退行性疾病的一个重要决定因素。突触功能障碍、神经元死亡和内在活动被认为是导致疾病状态下正常行为丧失的原因。然而，在疾病进展过程中，这些主要致病事件之间的相互作用还了解甚少。脊髓性肌萎缩症（SMA）是一种由广泛表达的 SMN 蛋白缺乏引起的神经退行性疾病，其特征是运动神经元死亡、骨骼肌萎缩，以及中枢和外周兴奋性突触的功能障碍和丧失。这些疾病标志导致脊髓感觉运动回路中的神经元活动总体减少。在这里，我们通过慢性使用美国食品和药物管理局批准的钾通道阻滞剂 4-氨基吡啶（4-AP）治疗，显示出增加神经元活性可改善严重 SMA 模型中雌雄两性的运动行为。4-AP 恢复了神经传递和本体感受突触和神经肌肉接头（NMJs）的数量，而对运动神经元死亡没有影响。此外，用药理学抑制 p53 依赖性运动神经元死亡进行 4-AP 治疗会产生附加效应，导致感觉运动回路病理学的完全纠正，并增强 SMA 小鼠的表型获益。我们的研究表明，4-AP 诱导的神经元活性增加可恢复感觉运动回路中的突触连接和功能，从而改善 SMA 运动表型。脊髓性肌萎缩症（SMA）是一种神经退行性疾病，其特征是突触丧失、运动神经元死亡以及脊髓感觉运动回路中的神经元活性降低。然而，这些是平行还是依赖事件尚不清楚。我们在这里表明，通过美国食品和药物管理局批准的药物 4-氨基吡啶（4-AP）长期增加神经元活性可挽救 SMA 小鼠模型中中枢和外周突触的数量和功能，从而改善感觉运动回路和运动行为。药理学抑制 p53（负责运动神经元死亡）和 4-AP 的联合治疗对 SMA 中的感觉运动回路具有相加的有益作用。因此，神经元活性恢复了突触连接，并显著改善了严重的 SMA 表型。
