Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
J Neurotrauma. 2011 Jul;28(7):1173-83. doi: 10.1089/neu.2010.1683.
Traumatic brain injury (TBI) causes selective neuronal damage in the hippocampus; however, the underlying mechanisms are still unclear. Post-traumatic alterations of ion channel activity, which actively regulate neuronal excitability and thus impact on excitotoxicity, may be involved in TBI-induced neuronal injury. Here we report that hyperpolarization-activated cation current (I(h)) contributes to the distinct vulnerability of hippocampal neurons in TBI. In a rat model of controlled cortical injury, moderate TBI produced neuronal death of both hippocampal CA3 neurons and mossy cells in the hilus, but not CA1 pyramidal cells. Treatment with lamotrigine, which enhances dendritic I(h), ameliorated TBI-induced neuronal damage to CA3 neurons and mossy cells. In contrast, intraventricular administration of I(h) channel blocker caused cell death in the CA1 region after TBI. Whole-cell recordings revealed that, differently from CA3 neurons, CA1 pyramidal cells expressed larger I(h) and exhibited a post-traumatic increase of I(h) amplitude. Moreover, blocking I(h) led to an increase of neuronal excitability, with greater effects seen in post-traumatic CA1 pyramidal cells than in CA3 neurons. In addition, the I(h) in mossy cells was dramatically inhibited early after TBI. Our findings indicate that differential changes of I(h) in hippocampal neurons may be one of the mechanisms of selective cell death, and that an enhancement of functional I(h) may protect hippocampal neurons against TBI.
创伤性脑损伤（TBI）会导致海马体中选择性神经元损伤；然而，其潜在机制尚不清楚。离子通道活性的创伤后改变主动调节神经元兴奋性，从而影响兴奋性毒性，可能参与 TBI 诱导的神经元损伤。在这里，我们报告超极化激活阳离子电流（I(h)）有助于 TBI 中海马神经元的独特易损性。在皮质控制损伤的大鼠模型中，中度 TBI 会导致海马 CA3 神经元和门区苔藓细胞死亡，但 CA1 锥体神经元不受影响。用拉莫三嗪治疗，可增强树突 I(h)，可改善 TBI 诱导的 CA3 神经元和苔藓细胞损伤。相比之下，脑室注射 I(h)通道阻滞剂会在 TBI 后引起 CA1 区的细胞死亡。全细胞膜片钳记录显示，与 CA3 神经元不同，CA1 锥体神经元表达更大的 I(h)，并表现出创伤后 I(h)幅度的增加。此外，阻断 I(h)会导致神经元兴奋性增加，在 TBI 后的 CA1 锥体神经元中比 CA3 神经元中更为明显。此外，TBI 后早期苔藓细胞中的 I(h) 会明显抑制。我们的研究结果表明，海马神经元中 I(h) 的差异变化可能是选择性细胞死亡的机制之一，而功能性 I(h) 的增强可能会保护海马神经元免受 TBI 的影响。
