TGF-β receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis
TGF-β receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis
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DOI：
10.1093/brain/awl317
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发表时间：
2007-02-01
期刊：
影响因子：
14.5
通讯作者：
Friedman, Alon
中科院分区：
文献类型：
--
作者：
Ivens, Sebastian;Kaufer, Daniela;Friedman, Alon
长期以来，人们已经认识到，对大脑皮层的损伤，如创伤、缺血或感染，可能导致癫痫的发展，癫痫是最常见的神经系统疾病之一。人类和动物研究表明，神经血管完整性的扰动和血脑屏障（BBB）的破坏导致神经元超同步和癫痫样活动，但这些过程的机制尚不清楚。在这项研究中，我们揭示了一种新的机制，癫痫发生在受伤的大脑。我们使用局灶性新皮质，持久的血脑屏障破坏或直接暴露于血清白蛋白的大鼠（51和13只动物，分别和26个对照），以及白蛋白暴露在体外脑切片。治疗后5-49天检查时，大多数治疗切片（72%，n = 189）显示超同步传播癫痫样场电位，但只有14%（n = 71）的对照切片显示类似的反应。我们证明，直接脑暴露于血清白蛋白与白蛋白摄取到星形胶质细胞，这是由转化生长因子β受体（TGF-β R）介导的。这种摄取之后是星形胶质细胞中内向整流钾（Kir 4.1）通道的下调，导致细胞外钾的缓冲减少。这反过来又导致细胞外钾的活动依赖性积累增加，导致促进N-甲基-D-天冬氨酸受体介导的神经元过度兴奋，并最终导致癫痫样活动。体内阻断TGF-β R可使暴露于白蛋白的脑中癫痫发生的可能性降低至29.3%（n = 41个切片，P < 0.05）。我们提出，上述级联事件后常见的脑损伤导致脑功能障碍，并最终癫痫，并建议TGF-β受体作为一个可能的治疗靶点。
It has long been recognized that insults to the cerebral cortex, such as trauma, ischaemia or infections, may result in the development of epilepsy, one of the most common neurological disorders. Human and animal studies have suggested that perturbations in neurovascular integrity and breakdown of the blood-brain barrier (BBB) lead to neuronal hypersynchronization and epileptiform activity, but the mechanisms underlying these processes are not known. In this study, we reveal a novel mechanism for epileptogenesis in the injured brain. We used focal neocortical, long-lasting BBB disruption or direct exposure to serum albumin in rats ( 51 and 13 animals, respectively, and 26 controls) as well as albumin exposure in brain slices in vitro. Most treated slices (72%, n = 189) displayed hypersynchronous propagating epileptiform field potentials when examined 5-49 days after treatment, but only 14% ( n = 71) of control slices showed similar responses. We demonstrate that direct brain exposure to serum albumin is associated with albumin uptake into astrocytes, which is mediated by transforming growth factor beta receptors (TGF-bRs). This uptake is followed by down regulation of inward-rectifying potassium (Kir 4.1) channels in astrocytes, resulting in reduced buffering of extracellular potassium. This, in turn, leads to activity-dependent increased accumulation of extracellular potassium, resulting in facilitated N-methyl-D-aspartate-receptor-mediated neuronal hyperexcitability and eventually epileptiform activity. Blocking TGF-bR in vivo reduces the likelihood of epileptogenesis in albumin-exposed brains to 29.3% ( n = 41 slices, P < 0.05). We propose that the above-described cascade of events following common brain insults leads to brain dysfunction and eventually epilepsy and suggest TGF-bRs as a possible therapeutic target.