Ferguson Adam R, Bolding Kevin A, Huie J Russell, Hook Michelle A, Santillano Daniel R, Miranda Rajesh C, Grau James W
Brain and Spinal Injury Center, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California 94110, USA.
J Neurosci. 2008 Nov 12;28(46):11939-49. doi: 10.1523/JNEUROSCI.3098-08.2008.
Neurons within the spinal cord can support several forms of plasticity, including response-outcome (instrumental) learning. After a complete spinal transection, experimental subjects are capable of learning to hold the hindlimb in a flexed position (response) if shock (outcome) is delivered to the tibialis anterior muscle when the limb is extended. This response-contingent shock produces a robust learning that is mediated by ionotropic glutamate receptors (iGluRs). Exposure to nociceptive stimuli that are independent of limb position (e.g., uncontrollable shock; peripheral inflammation) produces a long-term (>24 h) inhibition of spinal learning. This inhibition of plasticity in spinal learning is itself a form of plasticity that requires iGluR activation and protein synthesis. Plasticity of plasticity (metaplasticity) in the CNS has been linked to group I metabotropic glutamate receptors (subtypes mGluR1 and mGluR5) and activation of protein kinase C (PKC). The present study explores the role of mGluRs and PKC in the metaplastic inhibition of spinal cord learning using a combination of behavioral, pharmacological, and biochemical techniques. Activation of group I mGluRs was found to be both necessary and sufficient for metaplastic inhibition of spinal learning. PKC was activated by stimuli that inhibit spinal learning, and inhibiting PKC activity restored the capacity for spinal learning. Finally, a PKC inhibitor blocked the metaplastic inhibition of spinal learning produced by a group I mGluR agonist. The data strongly suggest that group I mGluRs control metaplasticity of spinal learning through a PKC-dependent mechanism, providing a potential therapeutic target for promoting use-dependent plasticity after spinal cord injury.
脊髓内的神经元能够支持多种形式的可塑性，包括反应-结果（工具性）学习。在完全脊髓横断后，如果在肢体伸展时向胫骨前肌施加电击（结果），实验对象能够学会将后肢保持在屈曲位置（反应）。这种与反应相关的电击会产生一种由离子型谷氨酸受体（iGluRs）介导的强大学习。暴露于与肢体位置无关的伤害性刺激（例如，不可控电击；外周炎症）会对脊髓学习产生长期（>24小时）抑制。这种对脊髓学习可塑性的抑制本身就是一种可塑性形式，需要iGluR激活和蛋白质合成。中枢神经系统中可塑性的可塑性（元可塑性）与I组代谢型谷氨酸受体（亚型mGluR1和mGluR5）以及蛋白激酶C（PKC）的激活有关。本研究使用行为、药理学和生化技术相结合的方法，探讨了mGluRs和PKC在脊髓学习的元可塑性抑制中的作用。发现I组mGluRs的激活对于脊髓学习的元可塑性抑制既是必要的也是充分的。PKC被抑制脊髓学习的刺激激活，抑制PKC活性可恢复脊髓学习能力。最后，一种PKC抑制剂阻断了I组mGluR激动剂产生的脊髓学习的元可塑性抑制。数据强烈表明，I组mGluRs通过PKC依赖性机制控制脊髓学习元可塑性，为促进脊髓损伤后依赖使用的可塑性提供了潜在的治疗靶点。
