Abstract
OBJECTIVE: Malformations of cortical development represent major causes of drug-resistant epilepsy, with mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy recognized as a distinct pathological entity. Pathogenic X-linked SLC35A2, encoding the uridine diphosphate-galactose transporter, has been implicated in this condition. In this study, we investigated the behavioral, electrophysiological, and cellular/molecular phenotypes associated with loss-of-function Slc35A2 mutations in oligodendrocytes. METHODS: A conditional knockout (cKO) mouse model was generated using an Olig2-specific promoter. Behavioral assessments included neurological scoring, open field, locomotor habituation, and pentylenetetrazole-induced seizure testing in 95 mice (31 female controls, 22 female cKO, 26 male controls, 16 male cKO), aged 4-18 weeks. Continuous electroencephalographic (EEG) studies were performed in eight control and eight 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. Males demonstrated more severe motor dysfunction compared to females due to the X-linked nature of Slc35a2. Video-EEG monitoring captured spontaneous electroclinical seizures in cKO mice, accompanied by frequent interictal spiking, despite preserved neuronal integrity. Histological and immunohistochemical evaluation revealed extensive subcortical hypomyelination, reactive gliosis, and significant reduction of Olig2-positive oligodendrocytes in the corpus callosum. SIGNIFICANCE: Our results demonstrate that loss of SLC35A2 function in oligodendrocytes is sufficient to reproduce pathological and clinical features observed in human mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy. Spontaneous seizures in the absence of direct neuronal genetic abnormalities highlight a central role for oligodendrocyte dysfunction and hypomyelination in epileptogenesis. These findings challenge the neuron-centric view of epilepsy and suggest that targeting glial dysfunction may offer novel therapeutic opportunities. Further studies are warranted to delineate cellular interactions driving epileptogenesis and to explore glia-centered treatment strategies for drug-resistant epilepsies.