Whole Transcriptome Screening Reveals Myelination Deficits in Dysplastic Human Temporal Neocortex

Abstract

Focal cortical dysplasias (FCDs) are local malformations of the human neocortex with strong epileptogenic potential. To investigate the underlying pathomechanisms, we performed a whole human transcriptome screening to compare the gene expression pattern of dysplastic versus nondysplastic temporal neocortex. Tissue obtained from FCD IIIa cases (mean age 20.5 years) who had undergone surgical treatment, due to intractable epilepsy, was compared with nondysplastic specimens (mean age 19.9 years) by means of Affymetrix arrays covering 28 869 genes. We found 211 differentially expressed genes (DEX) among which mainly genes important for oligodendrocyte differentiation and myelination were downregulated in FCD IIIa. These findings were confirmed as functionally important by Database for Annotation, Visualization, and Integrated Discovery (DAVID) analysis. The reduced expression of myelin-associated transcripts was confirmed for FCD Ia, IIa, and IIIa by real-time RT-qPCR. In addition, we found that the density of myelin basic protein mRNA-expressing oligodendrocytes and of 2',3'-cyclic nucleotide 3'-phosphodiesterase-positive myelin fibers was significantly reduced in dysplastic cortex. Moreover, high-resolution confocal imaging and 3D reconstruction revealed that the myelin fiber network was severely disorganized in dysplastic neocortex, indicating a disturbance of myelin sheath formation and maintenance in FCD.

Impaired oligodendroglial turnover is associated with myelin pathology in focal cortical dysplasia and tuberous sclerosis complex

“…This was in line with previous studies that reported similar results (23,35,49). It was also shown previously that myelin-related mRNA transcripts are reduced in the lesional cortex of FCD patients (10).…”

Oligodendrocyte lineage and myelination are compromised in the gray matter of focal cortical dysplasia type IIa

“…IHC was performed on either paraffin sections or cryosections as described before . Paraffin sections were pretreated (Tris‐buffered saline with 0.1% TritonX‐100, 1% bovine serum albumin [BSA, Sigma‐Aldrich] and incubated overnight in the rabbit monoclonal PDGFRα [platelet‐derived growth factor receptor alpha] primary antibody solution [1:500; Cell Signaling Technology] at 4°C).…”

“…Little is known about myelination disturbances in the context of FCD. Recently, we described for the first time a myelination defect in the cortical gray matter of FCD patients . So far, myelination abnormalities have been reported only for the white matter, in particular in FCD IIb cases .…”

Delayed myelination and neurodevelopment in male seizure‐prone versus seizure‐resistant rats

“…For instance, triple ( plp −/− , mbp −/− , mag −/− ) mutant mice exhibit hypomyelination and high frequency seizure onset by 3 months of age . In humans, comparative whole transcriptome screening of focal cortical dysplasias (neocortical malformations with strong epileptogenic potential) into nondysplastic temporal neocortex from epilepsy patients reportedly reduced expression of myelin‐associated transcripts including mbp , mog , and mag . Moreover, experimental studies on myelin‐deficient rats have demonstrated that lack of myelin results in regional axolemmal abnormalities such as axolemmal voltage‐gated sodium channels being more diffusely distributed at higher densities.…”

“…35 In humans, comparative whole transcriptome screening of focal cortical dysplasias (neocortical malformations with strong epileptogenic potential) into nondysplastic temporal neocortex from epilepsy patients reportedly reduced expression of myelinassociated transcripts including mbp, mog, and mag. 36 Moreover, experimental studies on myelin-deficient rats have demonstrated that lack of myelin results in regional axolemmal abnormalities such as axolemmal voltage-gated sodium channels being more diffusely distributed at higher densities. It is suggested that this ion flux increase across axolemma might lead to corresponding increased extracellular potassium levels, spontaneous activity due to random opening of the channels, low threshold for excitation, and ephaptic activation of neighboring axons.…”