Long-duration epilepsy affects cell morphology and glutamatergic synapses in type IIB focal cortical dysplasia
Long-duration epilepsy affects cell morphology and glutamatergic synapses in type IIB focal cortical dysplasia
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DOI：
10.1007/s00401-013-1143-4
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发表时间：
2013-08-01
影响因子：
12.7
通讯作者：
Battaglia, Giorgio Stefano
中科院分区：
文献类型：
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作者：
Finardi, Adele;Colciaghi, Francesca;Battaglia, Giorgio Stefano
为了研究严重癫痫对畸形皮质的假设影响，我们分析了 8 名 IIB 型局灶性皮质发育不良 (FCD) 患者的手术样本，并与 9 名非发育不良对照组的样本进行了比较。我们在适当的情况下使用体视定量方法研究了发育不良的神经元、神经元密度、球囊细胞、神经胶质细胞、谷氨酸突触输入以及 N-甲基-d-天冬氨酸 (NMDA) 受体亚基和相关膜相关鸟苷酸激酶 (MAGUK) 的表达。在所有 FCD 患者中，与细胞学正常的邻近区域相比，引起癫痫放电的发育不良区域的特征是较大的畸形神经元、神经元密度降低和谷氨酸能输入增加。研究发现，癫痫的持续时间与（a）畸形神经元大小、（b）神经元细胞密度降低以及（c）致癫痫/发育异常区域反应性神经胶质增生的程度直接相关。与谷氨酸能输入增加一致，蛋白质印迹显示，所有受检查的 FCD 患者致癫痫/发育不良区域的 NMDA 调节亚基和相关 MAGUK 蛋白均上调。总而言之，这些结果支持了这样的假设：癫痫本身改变了畸形的癫痫大脑的形态，也可能改变了功能。他们还表明，谷氨酸/NMDA/MAGUK 失调可能是改变大脑形态并诱导细胞死亡的细胞内触发因素。
To investigate hypothesized effects of severe epilepsy on malformed cortex, we analyzed surgical samples from eight patients with type IIB focal cortical dysplasia (FCD) in comparison with samples from nine non-dysplastic controls. We investigated, using stereological quantification methods, where appropriate, dysplastic neurons, neuronal density, balloon cells, glia, glutamatergic synaptic input, and the expression of N-methyl-d-aspartate (NMDA) receptor subunits and associated membrane-associated guanylate kinase (MAGUK). In all FCD patients, the dysplastic areas giving rise to epileptic discharges were characterized by larger dysmorphic neurons, reduced neuronal density, and increased glutamatergic inputs, compared to adjacent areas with normal cytology. The duration of epilepsy was found to correlate directly (a) with dysmorphic neuron size, (b) reduced neuronal cell density, and (c) extent of reactive gliosis in epileptogenic/dysplastic areas. Consistent with increased glutamatergic input, western blot revealed that NMDA regulatory subunits and related MAGUK proteins were up-regulated in epileptogenic/dysplastic areas of all FCD patients examined. Taken together, these results support the hypothesis that epilepsy itself alters morphology-and probably also function-in the malformed epileptic brain. They also suggest that glutamate/NMDA/MAGUK dysregulation might be the intracellular trigger that modifies brain morphology and induces cell death.