Molecular signaling mechanisms underlying epileptogenesis.
Molecular signaling mechanisms underlying epileptogenesis.
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DOI：
10.1126/stke.3562006re12
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发表时间：
2006-10-10
期刊：
影响因子：
--
通讯作者：
Leonard, A Soren
中科院分区：
文献类型：
--
作者：
McNamara, James O;Huang, Yang Zhong;Leonard, A Soren
癫痫是一种反复发作的疾病，是一种常见的、经常具有破坏性的神经系统疾病。可用的治疗只是有症状的，而且往往无效。了解癫痫发生，即正常大脑发生癫痫的过程，可能有助于确定可以预防癫痫的药物的分子靶点。这种疾病的许多获得性和遗传性原因已被确定，并已建立了各种体内和体外癫痫发生的模型。在这里，我们回顾了目前对癫痫发生的分子信号机制的见解，重点是边缘癫痫的发生。对不同模型的研究表明，神经元表面的各种受体的激活可以促进癫痫的发生；这些受体包括离子型和代谢型谷氨酸受体以及TrkB神经营养素受体。这些受体都在一种特定类型的皮质神经元--主神经元的树突棘--内的一个离散信号域膜上发现。这些受体中的任何一个的激活都会导致脊椎内钙离子浓度的增加。脊椎中发现的多种钙调节酶参与了癫痫的发生，其中包括非受体蛋白酪氨酸激酶Src和Fyn，丝氨酸-苏氨酸激酶[钙-钙调蛋白依赖的蛋白激酶II(CaMKII)]和磷酸酶(钙调神经磷酸酶)。星形胶质细胞和神经元之间的串扰促进树突状钙离子的增加和神经元的同步放电，这是癫痫样活动的标志。这一假说提出，边缘癫痫是由于神经元活动异常导致树突棘内钙离子浓度升高而引起的稳态反应的不良适应结果。
Epilepsy, a disorder of recurrent seizures, is a common and frequently devastating neurological condition. Available therapy is only symptomatic and often ineffective. Understanding epileptogenesis, the process by which a normal brain becomes epileptic, may help identify molecular targets for drugs that could prevent epilepsy. A number of acquired and genetic causes of this disorder have been identified, and various in vivo and in vitro models of epileptogenesis have been established. Here, we review current insights into the molecular signaling mechanisms underlying epileptogenesis, focusing on limbic epileptogenesis. Study of different models reveals that activation of various receptors on the surface of neurons can promote epileptogenesis; these receptors include ionotropic and metabotropic glutamate receptors as well as the TrkB neurotrophin receptor. These receptors are all found in the membrane of a discrete signaling domain within a particular type of cortical neuron--the dendritic spine of principal neurons. Activation of any of these receptors results in an increase Ca2+ concentration within the spine. Various Ca2+-regulated enzymes found in spines have been implicated in epileptogenesis; these include the nonreceptor protein tyrosine kinases Src and Fyn and a serine-threonine kinase [Ca2+-calmodulin-dependent protein kinase II (CaMKII)] and phosphatase (calcineurin). Cross-talk between astrocytes and neurons promotes increased dendritic Ca2+ and synchronous firing of neurons, a hallmark of epileptiform activity. The hypothesis is proposed that limbic epilepsy is a maladaptive consequence of homeostatic responses to increases of Ca2+ concentration within dendritic spines induced by abnormal neuronal activity.