PDF(Pubmed)
Abstract：
Muscle spasms are common in chronic spinal cord injury (SCI), posing challenges to rehabilitation and daily activities. Pharmacological management of spasms mostly targets suppression of excitatory inputs, an approach known to hinder motor recovery. To identify better targets, we investigated changes in inhibitory and excitatory synaptic inputs to motoneurons as well as motoneuron excitability in chronic SCI. We induced either a complete or incomplete SCI in adult mice of either sex and divided those with incomplete injury into low or high functional recovery groups. Their sacrocaudal spinal cords were then extracted and used to study plasticity below injury, with tissue from naive animals as a control. Electrical stimulation of the dorsal roots elicited spasm-like activity in preparations of chronic severe SCI but not in the control. To evaluate overall synaptic inhibition activated by sensory stimulation, we measured the rate-dependent depression of spinal root reflexes. We found inhibitory inputs to be impaired in chronic injury models. When synaptic inhibition was blocked pharmacologically, all preparations became clearly spastic, even the control. However, preparations with chronic injuries generated longer spasms than control. We then measured excitatory postsynaptic currents (EPSCs) in motoneurons during sensory-evoked spasms. The data showed no difference in the amplitude of EPSCs or their conductance among animal groups. Nonetheless, we found that motoneuron persistent inward currents activated by the EPSCs were increased in chronic SCI. These findings suggest that changes in motoneuron excitability and synaptic inhibition, rather than excitation, contribute to spasms and are better suited for more effective therapeutic interventions.Significance Statement Neural plasticity following spinal cord injury is crucial for recovery of motor function. Unfortunately, this process is blemished by maladaptive changes that can cause muscle spasms. Pharmacological alleviation of spasms without compromising the recovery of motor function has proven to be challenging. Here, we investigated changes in fundamental spinal mechanisms that can cause spasms post-injury. Our data suggest that the current management strategy for spasms is misdirected toward suppressing excitatory inputs, a mechanism that we found unaltered after injury, which can lead to further motor weakness. Instead, this study shows that more promising approaches might involve restoring synaptic inhibition or modulating motoneuron excitability.
摘要：
肌肉痉挛在慢性脊髓损伤（SCI）中很常见，对康复和日常活动构成挑战。痉挛的药理学管理主要针对抑制兴奋性输入，一种已知阻碍电机恢复的方法。为了确定更好的目标，我们调查了慢性SCI中运动神经元的抑制性和兴奋性突触输入以及运动神经元兴奋性的变化。我们在任何性别的成年小鼠中诱导了完全或不完全SCI，并将不完全损伤的小鼠分为低或高功能恢复组。然后将他们的骶尾部脊髓取出并用于研究损伤下的可塑性，用幼稚动物的组织作为对照。背根的电刺激在慢性严重SCI的制剂中引起痉挛样活动，但在对照中未引起。为了评估感觉刺激激活的整体突触抑制，我们测量了脊髓根反射的速率依赖性抑制。我们发现在慢性损伤模型中抑制输入受损。当突触抑制在药理学上被阻断时，所有的准备都变得明显痉挛，甚至是控制。然而,慢性损伤的制剂比对照组产生更长的痉挛。然后，我们在感觉诱发的痉挛期间测量运动神经元中的兴奋性突触后电流（EPSC）。数据显示EPSC的振幅或它们的电导在动物组之间没有差异。尽管如此，我们发现,在慢性SCI中,由EPSCs激活的运动神经元持续内向电流增加.这些发现表明运动神经元兴奋性和突触抑制的变化，而不是激励，有助于痉挛，更适合更有效的治疗干预。意义陈述脊髓损伤后的神经可塑性对于运动功能的恢复至关重要。不幸的是,这个过程因适应不良的变化而受到损害，这些变化会导致肌肉痉挛。在不损害运动功能恢复的情况下缓解痉挛的药理学已被证明是具有挑战性的。这里,我们调查了可能导致损伤后痉挛的基本脊柱机制的变化.我们的数据表明，目前的痉挛管理策略被错误地指向抑制兴奋性输入，我们发现受伤后没有改变的机制，这可能导致进一步的运动无力。相反，这项研究表明，更有希望的方法可能涉及恢复突触抑制或调节运动神经元兴奋性。
