Authors :
Presenting Author: Tiffany Bartel, BS – Cleveland Clinic
Chaitali Ghosh, PhD – Cleveland Clinic
Kathyn Bisaha, MS – Cleveland Clinic
Jean Khoury, MD – Cleveland Clinic
Ashley Nemes-Baran, PhD – Case Western Reserve University
Ingmar Blümcke, MD – University Hospitals Erlangen
Imad Najm, MD – Cleveland Clinic
Rationale:
Malformations of cortical development represent major causes of drug-resistant epilepsy, with mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy recently recognized as a distinct pathological entity. Somatic mutations in SLC35A2, encoding the uridine diphosphate-galactose transporter, have been implicated in this condition. In this study, we investigated the behavioral, electrophysiological, and cellular/molecular phenotypes associated with loss-of-function Slc35a2 mutations targeted to oligodendrocytes.
Methods:
A conditional knockout mouse model was generated using an Olig2-specific promoter. Behavioral assessments included neurological scoring, open field, locomotor habituation, and pentylenetetrazole-induced seizure testing in 85 mice (26 female controls, 17 female cKO, 26 male controls, 16 male cKO), aged 4-18 weeks. Continuous EEG studies were performed in 8 control and 8 cKO mice implanted with cortical electrodes. Histopathological analyses and immunohistochemistry were performed at postnatal days 15, 21, and 60.
Results:
Loss-of-function Slc35a2 mice exhibited significantly reduced body weight, progressive motor dysfunction, and reduced survival compared to controls. Video-EEG monitoring captured spontaneous electro-clinical seizures in cKO mice, accompanied by frequent interictal spiking, despite preserved neuronal integrity. Histological evaluation revealed extensive subcortical hypomyelination, reactive gliosis, and a significant reduction of Olig2-positive oligodendrocytes in the corpus. Transmission electron microscopy confirmed hypomyelination in genu of corpus callosum.
Conclusions:
Our results demonstrate that loss of SLC35A2 function in oligodendrocytes alone is sufficient to reproduce key pathological and clinical features observed in human mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy. Notably, the emergence of spontaneous seizures in the absence of direct neuronal genetic abnormalities highlights a central role for oligodendrocyte dysfunction and hypomyelination in epileptogenesis. These significant findings challenge the traditional neuron-centric view of epilepsy and suggest that targeting glial dysfunction may offer novel therapeutic opportunities.
Funding: This project was internally funded by the Cleveland Clinic Epilepsy Center.