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

Abstract

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. We found that in particular FCD IIb showed myelination disturbances such as increased numbers of myelinating oligodendrocytes (OLs) and an irregular and disorganized myelination pattern covering an enlarged area in comparison to FCD IIa and controls. 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. On the level of gene expression, FCD IIb presented with a significant up-regulation of myelin-associated mRNA synthesis in comparison to FCD IIa and by enhanced binding-capacities of the transcription factor MYRF to promoters of myelin-associated genes 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. Main pointsO_LIIn the gray matter of the frontal lobe, FCD IIa and FCD IIb are characterized by divergent signs of maladaptive myelination. C_LIO_LIFCD IIa presents with an ordinary radial fiber pattern, but with a reduced thickness of the myelin sheath around large diameter axons and with an attenuation of the myelin synthesis machinery. C_LIO_LIFCD IIb is characterized by an irregular and disorganized myelin fiber pattern, a higher density of myelinating oligodendrocytes and an elevated transcriptional turnover of myelin-associated genes. C_LI