Synaptic ultrastructural alterations in human focal cortical dysplasia: Insights from volume electron microscopy.

IF 6.6 1区 医学 Q1 CLINICAL NEUROLOGY
Epilepsia Pub Date : 2025-09-20 DOI:10.1111/epi.18626
Gyu Hyun Kim, Na-Young Seo, Seung-Ki Kim, Jae-Kyung Won, Yang Hoon Huh, Ji Yeoun Lee, Kea Joo Lee
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Abstract

Objective: Focal cortical dysplasia (FCD) is a developmental malformation of the cerebral cortex and a leading cause of drug-resistant epilepsy in children and young adults. Disruption of the excitation-inhibition (E-I) balance is a hallmark of neuronal hyperexcitability in FCD, yet the underlying synaptic ultrastructural changes remain poorly understood. This study aimed to investigate synaptic architecture and associated organelle alterations in epileptogenic cortex affected by FCD.

Methods: Using volume electron microscopy, we performed a detailed morphological assessment of synaptic density, size, and organelle distribution within synapses in the temporal cortical layer III of a patient with FCD. Comparative analyses were conducted between dysplastic and nondysplastic cortical regions.

Results: The dysplastic cortex exhibited a lower density of excitatory synapses but contained unusually large excitatory synapses with an increased number of synaptic vesicles. Inhibitory synapses were positioned farther from the nearest excitatory synapses along distal dendrites, potentially reducing the effectiveness of shunting inhibition in the dysplastic area. Presynaptic boutons in the dysplastic region showed increased mitochondrial density and abnormal mitochondrial morphology, whereas the proportion of postsynaptic protrusions containing a spine apparatus was reduced. These changes suggest potential deficits in intracellular calcium handling, metabolic homeostasis, and synaptic plasticity in the epileptogenic cortex. Additionally, maladaptive myelination was a prominent feature in the dysplastic region.

Significance: This study identifies distinct synaptic and subcellular structural abnormalities in FCD that may contribute to E-I imbalance and neuronal hyperexcitability. These findings provide novel ultrastructural insights into the pathophysiology of FCD and may inform future therapeutic strategies targeting synaptic and metabolic dysfunction.

人类局灶性皮质发育不良的突触超微结构改变:来自体积电子显微镜的见解。
目的:局灶性皮质发育不良(FCD)是一种大脑皮质发育畸形,是儿童和青少年耐药癫痫的主要原因。兴奋-抑制(E-I)平衡的破坏是FCD中神经元高兴奋性的一个标志,但潜在的突触超微结构变化仍然知之甚少。本研究旨在探讨FCD对致痫性皮质突触结构和相关细胞器的影响。方法:使用体积电子显微镜,我们对FCD患者颞皮质III层突触内的突触密度、大小和细胞器分布进行了详细的形态学评估。对比分析了发育不良和非发育不良的皮质区域。结果:发育不良皮层兴奋性突触密度降低,但兴奋性突触异常大,突触囊泡数量增加。抑制性突触位于离最近的兴奋性突触更远的地方,沿着远端树突,可能降低了发育不良区域分流抑制的有效性。发育不良区的突触前钮扣显示线粒体密度增加和线粒体形态异常,而突触后含有脊柱装置的突起比例减少。这些变化提示在细胞内钙处理、代谢稳态和突触可塑性方面存在潜在缺陷。此外,不适应髓鞘形成是发育不良区域的一个突出特征。意义:本研究发现FCD中明显的突触和亚细胞结构异常可能导致E-I失衡和神经元高兴奋性。这些发现为FCD的病理生理学提供了新的超微结构见解,并可能为未来针对突触和代谢功能障碍的治疗策略提供信息。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Epilepsia
Epilepsia 医学-临床神经学
CiteScore
10.90
自引率
10.70%
发文量
319
审稿时长
2-4 weeks
期刊介绍: Epilepsia is the leading, authoritative source for innovative clinical and basic science research for all aspects of epilepsy and seizures. In addition, Epilepsia publishes critical reviews, opinion pieces, and guidelines that foster understanding and aim to improve the diagnosis and treatment of people with seizures and epilepsy.
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