Brain Injury-Induced Synaptic Reorganization in Hilar Inhibitory Neurons Is Differentially Suppressed by Rapamycin.
Brain Injury-Induced Synaptic Reorganization in Hilar Inhibitory Neurons Is Differentially Suppressed by Rapamycin.
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DOI：
10.1523/eneuro.0134-17.2017
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发表时间：
2017-09
期刊：
影响因子：
3.4
通讯作者：
Smith BN
中科院分区：
文献类型：
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作者：
Butler CR;Boychuk JA;Smith BN
在创伤性脑损伤(TBI)后，雷帕霉素治疗可抑制哺乳动物(机械性)雷帕霉素(MTOR)活性靶点和与皮质兴奋性和癫痫敏感性改变相关的海马区突触重组的特定成分。然而，停止雷帕霉素治疗后再次出现癫痫发作表明，癫痫的发生受到了不完全的抑制。肺门抑制中间神经元调节齿状颗粒细胞(DGC)的活动，脑损伤后DGC和CA3锥体细胞的去新突触输入增加了它们的兴奋性，但雷帕霉素对损伤诱导的中间神经元可塑性的影响仅有部分报道。利用生长抑素能亚群表达增强型绿色荧光蛋白(EGFP)的转基因小鼠，检测了每日全身注射雷帕霉素(3 mg/kg)对控制性皮质冲击(CCI)诱导的局灶性脑损伤后肺门抑制间神经元兴奋性的影响。雷帕霉素治疗降低了损伤诱导的存活的EGFP+肺门中间神经元兴奋性的增加，但没有恢复正常。MTOR抑制后，损伤诱导的DGCs对谷氨酸选择性光刺激的反应性增加降至正常水平，但损伤后CA3锥体细胞活动引起的突触兴奋增加不受雷帕霉素的影响。脑损伤后抑制回路中突触重组的不完全抑制可能导致海马区的过度兴奋性，并在mTOR抑制停止后最终导致致痫过程的重新出现。此外，mTOR抑制对CCI后突触重组的细胞选择性效应表明，雷帕霉素治疗可能改变了某些模型的癫痫发生，而不是其他模型。
Following traumatic brain injury (TBI), treatment with rapamycin suppresses mammalian (mechanistic) target of rapamycin (mTOR) activity and specific components of hippocampal synaptic reorganization associated with altered cortical excitability and seizure susceptibility. Reemergence of seizures after cessation of rapamycin treatment suggests, however, an incomplete suppression of epileptogenesis. Hilar inhibitory interneurons regulate dentate granule cell (DGC) activity, and de novo synaptic input from both DGCs and CA3 pyramidal cells after TBI increases their excitability but effects of rapamycin treatment on the injury-induced plasticity of interneurons is only partially described. Using transgenic mice in which enhanced green fluorescent protein (eGFP) is expressed in the somatostatinergic subset of hilar inhibitory interneurons, we tested the effect of daily systemic rapamycin treatment (3 mg/kg) on the excitability of hilar inhibitory interneurons after controlled cortical impact (CCI)-induced focal brain injury. Rapamycin treatment reduced, but did not normalize, the injury-induced increase in excitability of surviving eGFP+ hilar interneurons. The injury-induced increase in response to selective glutamate photostimulation of DGCs was reduced to normal levels after mTOR inhibition, but the postinjury increase in synaptic excitation arising from CA3 pyramidal cell activity was unaffected by rapamycin treatment. The incomplete suppression of synaptic reorganization in inhibitory circuits after brain injury could contribute to hippocampal hyperexcitability and the eventual reemergence of the epileptogenic process upon cessation of mTOR inhibition. Further, the cell-selective effect of mTOR inhibition on synaptic reorganization after CCI suggests possible mechanisms by which rapamycin treatment modifies epileptogenesis in some models but not others.