Donkels Catharina, Häussler Ute, Huber Susanne, Tiesmeyer Nina, Demerath Theo, Scheiwe Christian, Shah Mukesch J, Heers Marcel, Urbach Horst, Schulze-Bonhage Andreas, Prinz Marco, Vlachos Andreas, Beck Jürgen, Nakagawa Julia M, Haas Carola A
Faculty of Medicine, Experimental Epilepsy Research, Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany.
Faculty of Medicine, Translational Epilepsy Research, Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany.
Glia. 2025 May;73(5):928-947. doi: 10.1002/glia.24662. Epub 2024 Dec 24.
Focal cortical dysplasias (FCDs) are local malformations of the human neocortex and a leading cause of intractable epilepsy. FCDs are classified into different subtypes including FCD IIa and IIb, characterized by a blurred gray-white matter boundary or a transmantle sign indicating abnormal white matter myelination. Recently, we have shown that myelination is also compromised in the gray matter of FCD IIa of the temporal lobe. Since myelination is key for brain function, which is imbalanced in epilepsy, in the current study, we investigated myelination in the gray matter of FCD IIa and IIb from the frontal lobe on the morphological, ultrastructural, and transcriptional level. We found that FCD IIa presents with an ordinary radial myelin fiber pattern, but with a reduced thickness of myelin sheaths of 500-1000 nm thick axons in comparison to FCD IIb and with an attenuation of the myelin synthesis machinery. In contrast, FCD IIb showed an irregular and disorganized myelination pattern covering an enlarged area in comparison to FCD IIa and controls and with increased numbers of myelinating oligodendrocytes (OLs). FCD IIb had significantly thicker myelin sheaths of large caliber axons (above 1000 nm) when compared to FCD IIa. Accordingly, FCD IIb showed a significant up-regulation of myelin-associated mRNAs in comparison to FCD IIa and enhanced binding capacities of the transcription factor MYRF to target sites in myelin-associated genes. These data indicate that FCD IIa and IIb are characterized by a differential dysregulation of myelination in the gray matter of the frontal lobe.
局灶性皮质发育不良（FCDs）是人类新皮质的局部畸形，也是顽固性癫痫的主要病因。FCDs分为不同亚型，包括FCD IIa和IIb，其特征为灰白质边界模糊或有跨皮质征，提示白质髓鞘形成异常。最近，我们发现颞叶FCD IIa的灰质中髓鞘形成也受到损害。由于髓鞘形成对脑功能至关重要，而脑功能在癫痫中失衡，因此在本研究中，我们从形态学、超微结构和转录水平研究了额叶FCD IIa和IIb灰质中的髓鞘形成。我们发现，FCD IIa呈现出普通的放射状髓鞘纤维模式，但与FCD IIb相比，500 - 1000纳米厚轴突的髓鞘厚度减小，且髓鞘合成机制减弱。相比之下，FCD IIb显示出不规则且紊乱的髓鞘形成模式，与FCD IIa和对照组相比，其覆盖面积增大，且髓鞘形成的少突胶质细胞（OLs）数量增加。与FCD IIa相比，FCD IIb中粗口径轴突（超过1000纳米）的髓鞘明显更厚。因此，与FCD IIa相比，FCD IIb中髓鞘相关mRNA显著上调，转录因子MYRF与髓鞘相关基因靶位点的结合能力增强。这些数据表明，FCD IIa和IIb的特征是额叶灰质中髓鞘形成的差异性失调。
