Department of Neurology, School of Medicine, and.
Anticonvulsant Drug Development Program, Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, Utah, USA.
J Clin Invest. 2020 Nov 2;130(11):6005-6020. doi: 10.1172/JCI134793.
Edema is an important target for clinical intervention after traumatic brain injury (TBI). We used in vivo cellular resolution imaging and electrophysiological recording to examine the ionic mechanisms underlying neuronal edema and their effects on neuronal and network excitability after controlled cortical impact (CCI) in mice. Unexpectedly, we found that neuronal edema 48 hours after CCI was associated with reduced cellular and network excitability, concurrent with an increase in the expression ratio of the cation-chloride cotransporters (CCCs) NKCC1 and KCC2. Treatment with the CCC blocker bumetanide prevented neuronal swelling via a reversal in the NKCC1/KCC2 expression ratio, identifying altered chloride flux as the mechanism of neuronal edema. Importantly, bumetanide treatment was associated with increased neuronal and network excitability after injury, including increased susceptibility to spreading depolarizations (SDs) and seizures, known agents of clinical worsening after TBI. Treatment with mannitol, a first-line edema treatment in clinical practice, was also associated with increased susceptibility to SDs and seizures after CCI, showing that neuronal volume reduction, regardless of mechanism, was associated with an excitability increase. Finally, we observed an increase in excitability when neuronal edema normalized by 1 week after CCI. We conclude that neuronal swelling may exert protective effects against damaging excitability in the aftermath of TBI and that treatment of edema has the potential to reverse these effects.
脑水肿是创伤性脑损伤（TBI）后临床干预的一个重要靶点。我们使用活体细胞分辨率成像和电生理记录技术，研究了离子机制在控制皮质撞击（CCI）后神经元水肿及其对神经元和网络兴奋性的影响。出乎意料的是，我们发现CCI 后 48 小时的神经元水肿与细胞和网络兴奋性降低有关，同时阳离子-氯离子共转运体（CCCs）NKCC1 和 KCC2 的表达比率增加。使用 CCC 阻断剂布美他尼治疗可通过逆转 NKCC1/KCC2 表达比率来防止神经元肿胀，表明氯离子通量的改变是神经元水肿的机制。重要的是，布美他尼治疗后损伤后的神经元和网络兴奋性增加，包括对扩散性去极化（SD）和癫痫发作的易感性增加，这是 TBI 后临床恶化的已知因素。在临床实践中作为一线水肿治疗的甘露醇治疗也与 CCI 后 SD 和癫痫发作的易感性增加有关，表明神经元体积减少，无论机制如何，都与兴奋性增加有关。最后，我们观察到 CCI 后 1 周神经元水肿正常化时兴奋性增加。我们得出结论，神经元肿胀可能在 TBI 后对破坏性兴奋性产生保护作用，而水肿的治疗有可能逆转这些作用。
