Critical role of trkB receptors in reactive axonal sprouting and hyperexcitability after axonal injury
Critical role of trkB receptors in reactive axonal sprouting and hyperexcitability after axonal injury
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DOI：
10.1152/jn.00869.2012
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发表时间：
2013-02-01
影响因子：
2.5
通讯作者：
Thompson, Scott M.
中科院分区：
文献类型：
--
作者：
Aungst, Stephanie;England, Pamela M.;Thompson, Scott M.
昂斯特·S (Aungst S)，英国首相，汤普森·SM (Thompson SM)。 trkB 受体在轴突损伤后反应性轴突出芽和过度兴奋中的关键作用。 J Neurophysiol 109: 813-824, 2013。首次发表于 2012 年 11 月 14 日； doi:10.1152/jn.00869.2012.-创伤性脑损伤 (TBI) 会导致许多长期神经并发症。其中一些病症，例如创伤后癫痫，其特征是兴奋性增加，通常在持续数月至数年的潜伏期后出现，这表明缓慢的损伤诱发过程至关重要。我们测试了这样的假设：trkB 激活部分通过促进反应性轴突萌芽来促进延迟性损伤诱导的过度兴奋。我们在 trkB 受体 (trkB(F616A)) 中引入了突变，使其易于受到新型小分子 1NMPP1 的抑制，通过横断敲入小鼠的 Schaffer 侧支通路来模拟穿透性 TBI。我们观察到损伤后 1 天 CA3 区的 trkB 激活增加，并且损伤后 7 天轴突生长标志物 GAP43 的表达增加。假手术小鼠和损伤小鼠的急性切片中 CA3 区锥体层的细胞外场电位在对照盐水中正常。在轻度促惊厥的条件下观察到群体峰值的异常爆发，但仅在 7-21 天前病变小鼠的切片中观察到，而在对照小鼠的切片中则没有。损伤后 7 天全身施用 1NMPP1 可以减少 trkB 激活、GAP43 上调和过度兴奋。在未经治疗的小鼠中，从 CA3 区到 CA1 区的突触传递在损伤后 7 天恢复，但在用 1NMPP1 治疗的小鼠中则没有。我们得出的结论是，trkB 受体激活和反应性轴突出芽是损伤引起的过度兴奋的关键因素，并可能导致 TBI 的神经系统并发症。
Aungst S, England PM, Thompson SM. Critical role of trkB receptors in reactive axonal sprouting and hyperexcitability after axonal injury. J Neurophysiol 109: 813-824, 2013. First published November 14, 2012; doi:10.1152/jn.00869.2012.-Traumatic brain injury (TBI) causes many long-term neurological complications. Some of these conditions, such as posttraumatic epilepsy, are characterized by increased excitability that typically arises after a latent period lasting from months to years, suggesting that slow injury-induced processes are critical. We tested the hypothesis that trkB activation promotes delayed injury-induced hyperexcitability in part by promoting reactive axonal sprouting. We modeled penetrative TBI with transection of the Schaffer collateral pathway in knock-in mice having an introduced mutation in the trkB receptor (trkB(F616A)) that renders it susceptible to inhibition by the novel small molecule 1NMPP1. We observed that trkB activation was increased in area CA3 1 day after injury and that expression of a marker of axonal growth, GAP43, was increased 7 days after lesion. Extracellular field potentials in stratum pyramidale of area CA3 in acute slices from sham-operated and lesioned mice were normal in control saline. Abnormal bursts of population spikes were observed under conditions that were mildly proconvulsive but only in slices taken from mice lesioned 7-21 days earlier and not in slices from control mice. trkB activation, GAP43 upregulation, and hyperexcitability were diminished by systemic administration of 1NMPP1 for 7 days after the lesion. Synaptic transmission from area CA3 to area CA1 recovered 7 days after lesion in untreated mice but not in mice treated with 1NMPP1. We conclude that trkB receptor activation and reactive axonal sprouting are critical factors in injury-induced hyperexcitability and may contribute to the neurological complications of TBI.