Neuronal ion and volume shifts after acute brain injury

NINDS为我提供了研究神经元离子稳态、GABA信号和 癫痫发病30年。这种持续的支持使板凳到板凳的成功完成 对新生儿癫痫的一种新疗法的床边翻译，这种疗法对可用药基本上没有反应 治疗。这种新的疗法是基于对神经元阴离子稳态的操纵，这有助于 GABAA受体信号和音量调节。这些研究使我们认识到 细胞内外阴离子大分子对神经元氯化物和体积的影响 动态平衡。细胞内外离子和渗透力之间的微妙平衡很容易实现。 由于膜通透性的变化或膜一侧渗透分子的动员而引起的紊乱。这里 我们认为，脑损伤导致了这两种扰动，从而对 神经元容量调节。在成熟的大脑中，这会导致细胞毒性水肿和脑肿胀， 没有治愈的方法，只有适度有效的对症治疗。在早产儿的大脑中， 成交量的变化同样有问题，但我们的分析预测，它们在符号上是相反的。我们 认为未成熟神经元在损伤后收缩，导致磁共振弥散加权成像信号缺失以及局部 组织收缩，血管扩张，和潜在的出血。这些影响导致了当前的 照顾极低出生体重儿的问题：脑损伤很猖獗，但直接原因是 不清楚，因为无法用核磁共振或超声波对损伤进行成像。只有后果 (出血和萎缩)可见。我们建议研究损伤后的神经元离子和体积移位。 在体外和体内，使用先进的成像技术和离子敏感的荧光团。结果将会是 为这些对受损神经元体积变化的新见解是否做好准备提供了强有力的指标 用于翻译为新的治疗策略，既可用于发育中的脑损伤，也可用于成熟的脑损伤。

The NINDS has provided me the opportunity to study neuronal ion homeostasis, GABA signaling, and epileptogenesis for 30 years. That sustained support enabled the completion of a successful bench-to- bedside translation of a new therapy for neonatal seizures, which are largely unresponsive to available therapies. This new therapy is based on manipulation of neuronal anion homeostasis, which subserves both GABAA receptor signaling and volume regulation. These studies led us to appreciate the magnitude of the Donnan effects of intra and extracellular anionic macromolecules on neuronal chloride and volume homeostasis. The delicate balance between intra and extracellular ionic and osmotic forces could be easily upset by changes in membrane permeability or mobilization of osmoles on one side of the membrane. Here we propose that brain injury results in both of these perturbations, with consequent catastrophic effects on neuronal volume regulation. In the mature brain, this results in cytotoxic edema and brain swelling, for which there are no curative and only modestly effective symptomatic therapies. In the premature brain, volume changes are equally problematic, but our analyses predict that they are opposite in sign. We propose that immature neurons shrink after injury, resulting in an absent MRI DWI signature as well as local tissue shrinkage, vascular stretch, and potential hemorrhage. These effects contribute to the current problems in the care of very low birthweight infants: brain injury is rampant, but the immediate causes are not clear because the injury cannot be imaged with MRI or ultrasound. Only the consequences (hemorrhage and atrophy) are visible. We propose to investigate neuronal ion and volume shifts after injury in vitro and in vivo, using advanced imaging techniques and ion-sensitive fluorophores. The results will provide robust indicators as to whether these new insights into volume shifts in injured neurons are ready for translation to novel therapeutic strategies for both the developing and the mature injured brain.