Swann J W, Al-Noori S, Jiang M, Lee C L
Cain Foundation Laboratories, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
Hippocampus. 2000;10(5):617-25. doi: 10.1002/1098-1063(2000)10:5<617::AID-HIPO13>3.0.CO;2-R.
Studies of neurons from human epilepsy tissue and comparable animal models of focal epilepsy have consistently reported a marked decrease in dendritic spine density on hippocampal and neocortical pyramidal cells. Spine loss is often accompanied by focal varicose swellings or beading of dendritic segments. An ongoing excitotoxic injury of dendrites (dendrotoxicity), produced by excessive release of glutamate during seizures, is often assumed to produce these abnormalities. Indeed, application of glutamate receptor agonists to dendrites can produce both spine loss and beading. However, the cellular mechanisms underlying the two processes appear to be different. One recent study suggests NMDA-induced spine loss is produced by Ca2+-mediated alterations of the spine cytoskeleton. In contrast, dendritic beading is not dependent on extracellular Ca2+; instead, it appears to be produced by the movement of Na+ and Cl- intracellularly and an obligate movement of water to maintain osmolarity. A decrease in dendritic spine density was recently reported in a model of recurrent focal seizures in early life. Unlike results from other models, dendritic beading was not observed, and other signs of neuronal injury and death were absent. Thus, additional mechanisms to those of excitotoxicity may produce dendritic spine loss in epileptic tissue. A hypothesis is presented that spine loss can be a product of a partial deafferentation of pyramidal cells, resulting from an activity-dependent pruning of neuronal connectivity induced by recurring seizures. The dendritic abnormalities observed in epilepsy are commonly suggested to be a product and not a cause of epilepsy. However, anatomical remodeling may be accompanied by alterations in molecular expression and targeting of both voltage- and ligand-gated channels in dendrites. It is conceivable that such changes could contribute to the neuronal hyperexcitability of epilepsy.
对来自人类癫痫组织以及局灶性癫痫可比动物模型的神经元研究一致报告称，海马体和新皮质锥体细胞上的树突棘密度显著降低。树突棘丢失通常伴随着树突节段的局灶性静脉曲张样肿胀或串珠样改变。癫痫发作期间谷氨酸过度释放所产生的持续性树突兴奋性毒性损伤（树突毒性）通常被认为会导致这些异常。事实上，将谷氨酸受体激动剂应用于树突可导致树突棘丢失和串珠样改变。然而，这两个过程背后的细胞机制似乎有所不同。最近的一项研究表明，NMDA诱导的树突棘丢失是由Ca2+介导的树突棘细胞骨架改变所致。相比之下，树突串珠样改变不依赖于细胞外Ca2+；相反，它似乎是由Na+和Cl-向细胞内移动以及为维持渗透压而必然发生的水移动所产生的。最近在早期复发性局灶性癫痫发作模型中报告了树突棘密度降低。与其他模型的结果不同，未观察到树突串珠样改变，也没有其他神经元损伤和死亡的迹象。因此，除了兴奋性毒性机制外，可能还有其他机制导致癫痫组织中的树突棘丢失。本文提出一个假说，即树突棘丢失可能是锥体细胞部分传入缺失的产物，这是由反复癫痫发作诱导的神经元连接性活动依赖性修剪所致。癫痫中观察到的树突异常通常被认为是癫痫的产物而非病因。然而，解剖重塑可能伴随着树突中电压门控通道和配体门控通道的分子表达及靶向改变。可以想象，这些变化可能导致癫痫的神经元过度兴奋性。
