Focal cortical dysplasia type II-dependent maladaptive myelination in the human frontal lobe

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, we investigated whether deficient myelination is a feature affecting also other FCD subtypes and brain areas. Here, we focused on the gray matter of FCD IIa and IIb from the frontal lobe. We applied in situ hybridization, immunohistochemistry and electron microscopy to quantify oligodendrocytes, to visualize the myelination pattern and to determine ultrastructurally the axon diameter and the myelin sheath thickness. In addition, we analyzed the transcriptional regulation of myelin-associated transcripts by real-time RT-qPCR and chromatin immunoprecipitation (ChIP). We show that densities of myelinating oligodendrocytes and the extension of myelinated fibers up to layer II were unaltered in both FCD types but myelinated fibers appeared fractured mainly in FCD IIa. Interestingly, both FCD types presented with larger axon diameters when compared to controls. A significant correlation of axon diameter and myelin sheath thickness was found for FCD IIb and controls, whereas in FCD IIa large caliber axons were less myelinated. This was mirrored by a down-regulation of myelin-associated mRNAs and by reduced binding-capacities of the transcription factor MYRF to promoters of myelin-associated genes. FCD IIb, however, had significantly elevated transcript levels and MYRF-binding capacities reflecting the need for more myelin due to increased axon diameters. These data show that FCD IIa and IIb are characterized by divergent signs of maladaptive myelination which may contribute to the epileptic phenotype and underline the view of separate disease entities.