Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.
Physical Therapy and Human Movement Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States.
Front Neural Circuits. 2021 Mar 23;15:642111. doi: 10.3389/fncir.2021.642111. eCollection 2021.
Spinal cord injury (SCI) results in not only the loss of voluntary muscle control, but also in the presence of involuntary movement or spasms. These spasms post-SCI involve hyperexcitability in the spinal motor system. Hyperactive motor commands post SCI result from enhanced excitatory postsynaptic potentials (EPSPs) and persistent inward currents in voltage-gated L-type calcium channels (LTCCs), which are reflected in evoked root reflexes with different timings. To further understand the contributions of these cellular mechanisms and to explore the involvement of LTCC subtypes in SCI-induced hyperexcitability, we measured root reflexes with ventral root recordings and motoneuron activities with intracellular recordings in an preparation using a mouse model of chronic SCI (cSCI). Specifically, we explored the effects of 1-(3-chlorophenethyl)-3-cyclopentylpyrimidine-2,4,6-(1H,3H,5H)-trione (CPT), a selective negative allosteric modulator of Ca1.3 LTCCs. Our results suggest a hyperexcitability in the spinal motor system in these SCI mice. Bath application of CPT displayed slow onset but dose-dependent inhibition of the root reflexes with the strongest effect on LLRs. However, the inhibitory effect of CPT is less potent in cSCI mice than in acute SCI (aSCI) mice, suggesting changes either in composition of Ca1.3 or other cellular mechanisms in cSCI mice. For intracellular recordings, the intrinsic plateau potentials, was observed in more motoneurons in cSCI mice than in aSCI mice. CPT inhibited the plateau potentials and reduced motoneuron firings evoked by intracellular current injection. These results suggest that the LLR is an important target and that CPT has potential in the therapy of SCI-induced muscle spasms.
脊髓损伤 (SCI) 不仅导致随意肌肉控制的丧失，还导致不自主运动或痉挛的出现。SCI 后的这些痉挛涉及脊髓运动系统的过度兴奋。SCI 后过度活跃的运动指令源于电压门控 L 型钙通道 (LTCC) 中增强的兴奋性突触后电位 (EPSP) 和持续内向电流，这反映在具有不同定时的诱发神经根反射中。为了进一步了解这些细胞机制的贡献，并探索 LTCC 亚型在 SCI 诱导的过度兴奋中的参与，我们使用慢性 SCI (cSCI) 小鼠模型在一个 制剂中通过记录腹根反射和细胞内记录运动神经元活动来测量根反射。具体来说，我们探讨了 1-(3-氯苯乙基)-3-环戊基嘧啶-2,4,6-(1H,3H,5H)-三酮 (CPT) 的作用，这是一种 Ca1.3 LTCC 的选择性负变构调节剂。我们的结果表明，这些 SCI 小鼠的脊髓运动系统存在过度兴奋。CPT 的浴应用显示出缓慢的起始但剂量依赖性的根反射抑制作用，对 LLR 的抑制作用最强。然而，CPT 的抑制作用在 cSCI 小鼠中比在急性 SCI (aSCI) 小鼠中较弱，这表明在 cSCI 小鼠中 Ca1.3 的组成或其他细胞机制发生了变化。对于细胞内记录，在 cSCI 小鼠中观察到更多运动神经元的固有平台电位，而在 aSCI 小鼠中则没有。CPT 抑制平台电位并减少细胞内电流注射诱发的运动神经元放电。这些结果表明，LLR 是一个重要的靶点，CPT 具有治疗 SCI 引起的肌肉痉挛的潜力。
