Centre for Brain Repair, University of Cambridge, Cambridge CB2 0PY, United Kingdom.
J Neurosci. 2011 Dec 7;31(49):17788-99. doi: 10.1523/JNEUROSCI.4308-11.2011.
Elevating spinal levels of neurotrophin NT-3 (NT3) while increasing expression of the NR2D subunit of the NMDA receptor using a HSV viral construct promotes formation of novel multisynaptic projections from lateral white matter (LWM) axons to motoneurons in neonates. However, this treatment is ineffective after postnatal day 10. Because chondroitinase ABC (ChABC) treatment restores plasticity in the adult CNS, we have added ChABC to this treatment and applied the combination to adult rats receiving a left lateral hemisection (Hx) at T8. All hemisected animals initially dragged the ipsilateral hindpaw and displayed abnormal gait. Rats treated with ChABC or NT3/HSV-NR2D recovered partial hindlimb locomotor function, but animals receiving combined therapy displayed the most improved body stability and interlimb coordination [Basso-Beattie-Bresnahan (BBB) locomotor scale and gait analysis]. Electrical stimulation of the left LWM at T6 did not evoke any synaptic response in ipsilateral L5 motoneurons of control hemisected animals, indicating interruption of the white matter. Only animals with the full combination treatment recovered consistent multisynaptic responses in these motoneurons indicating formation of a detour pathway around the Hx. These physiological findings were supported by the observation of increased branching of both cut and intact LWM axons into the gray matter near the injury. ChABC-treated animals displayed more sprouting than control animals and those receiving NT3/HSV-NR2D; animals receiving the combination of all three treatments showed the most sprouting. Our results indicate that therapies aimed at increasing plasticity, promoting axon growth and modulating synaptic function have synergistic effects and promote better functional recovery than if applied individually.
使用 HSV 病毒构建物提高神经营养因子 NT-3（NT3）的脊髓水平，同时增加 NMDA 受体的 NR2D 亚基的表达，可促进外侧白质（LWM）轴突向新生动物运动神经元形成新的多突触投射。然而，这种治疗在出生后第 10 天之后就无效了。因为软骨素酶 ABC（ChABC）治疗可恢复成年中枢神经系统的可塑性，所以我们将 ChABC 添加到这种治疗中，并将组合应用于接受 T8 左侧半横切（Hx）的成年大鼠。所有半横切动物最初都拖着同侧后脚，表现出异常步态。用 ChABC 或 NT3/HSV-NR2D 治疗的大鼠恢复了部分后肢运动功能，但接受联合治疗的动物表现出了最明显的身体稳定性和肢体间协调性的改善[Basso-Beattie-Bresnahan（BBB）运动量表和步态分析]。电刺激 T6 左侧 LWM 不会在对照半横切动物的同侧 L5 运动神经元中引起任何突触反应，表明白质中断。只有接受完整联合治疗的动物才能恢复这些运动神经元中一致的多突触反应，表明形成了绕过 Hx 的旁路。这些生理发现得到了观察结果的支持，即在损伤附近的灰质中，无论是切断的还是完整的 LWM 轴突都增加了分支。ChABC 治疗的动物比对照动物和接受 NT3/HSV-NR2D 治疗的动物表现出更多的发芽；接受所有三种治疗组合的动物显示出最多的发芽。我们的结果表明，旨在增加可塑性、促进轴突生长和调节突触功能的治疗具有协同作用，可促进比单独应用更好的功能恢复。
