Exercise Modulates Chloride Homeostasis after Spinal Cord Injury
Exercise Modulates Chloride Homeostasis after Spinal Cord Injury
复制标题
DOI：
10.1523/jneurosci.0678-14.2014
复制
发表时间：
2014-07-02
影响因子：
5.3
通讯作者：
Houle, John D.
中科院分区：
文献类型：
--
作者：
Cote, Marie-Pascale;Gandhi, Sapan;Houle, John D.
基于活动的疗法通常被纳入脊髓损伤 (SCI) 康复计划中，因为它们可以减少反射亢进和痉挛。然而，人们对运动调节脊柱通路活动以减少痉挛和改善功能恢复的机制知之甚少。 GABA 对突触后靶点作用的持续改变是中枢神经系统损伤（包括 SCI）的标志。 GABA 的作用取决于细胞内氯离子浓度，这很大程度上取决于两种阳离子-氯离子协同转运蛋白 (CCC) KCC2 和 NKCC1 的表达，它们分别充当氯离子输出器和输入器。我们假设 SCI 后运动对反射亢进的减少依赖于氯离子稳态的恢复。 Sprague Dawley 大鼠在 T12 时接受脊髓横断，并被分配到 SCI-7d、SCI-14d、SCI-14d + 运动、SCI-28d、SCI-28d + 运动或 SCI-56d 组。在最终实验中，刺激胫神经后记录了骨间肌的 H 反射，并评估了低频依赖性抑郁症 (FDD)。我们提供的证据表明，运动可使腰部脊髓的脊髓兴奋性以及 KCC2 和 NKCC1 水平恢复到正常水平。使用 KCC2 阻断剂 DIOA 急剧改变氯离子排出掩盖了运动对 FDD 的影响，而用布美他尼阻断 NKCC1 使 SCI 后的 FDD 恢复到完整水平。我们的结果表明，运动有助于 SCI 后恢复氯离子稳态，从而促进反射恢复和内源性抑制的恢复。这为 CCC 提供了支持，作为与康复计划相结合时可以改善功能恢复的途径的一部分。
Activity-based therapies are routinely integrated in spinal cord injury (SCI) rehabilitation programs because they result in a reduction of hyperreflexia and spasticity. However, the mechanisms by which exercise regulates activity in spinal pathways to reduce spasticity and improve functional recovery are poorly understood. Persisting alterations in the action of GABA on postsynaptic targets is a signature of CNS injuries, including SCI. The action of GABA depends on the intracellular chloride concentration, which is determined largely by the expression of two cation-chloride cotransporters (CCCs), KCC2 and NKCC1, which serve as chloride exporters and importers, respectively. We hypothesized that the reduction in hyperreflexia with exercise after SCI relies on a return to chloride homeostasis. Sprague Dawley rats received a spinal cord transection at T12 and were assigned to SCI-7d, SCI-14d, SCI-14d + exercise, SCI-28d, SCI-28d + exercise, or SCI-56d groups. During a terminal experiment, H-reflexes were recorded from interosseus muscles after stimulation of the tibial nerve and the low-frequency-dependent depression (FDD) was assessed. We provide evidence that exercise returns spinal excitability and levels of KCC2 and NKCC1 toward normal levels in the lumbar spinal cord. Acutely altering chloride extrusion using the KCC2 blocker DIOA masked the effect of exercise on FDD, whereas blocking NKCC1 with bumetanide returned FDD toward intact levels after SCI. Our results indicate that exercise contributes to reflex recovery and restoration of endogenous inhibition through a return to chloride homeostasis after SCI. This lends support for CCCs as part of a pathway that could be manipulated to improve functional recovery when combined with rehabilitation programs.