Loss ofSlc35a2alters development of the mouse cerebral cortex

Abstract

AbstractBrain somatic variants inSLC35A2are associated with clinically drug-resistant epilepsy and developmental brain malformations, including mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE).SLC35A2encodes a uridine diphosphate galactose translocator that is essential for protein glycosylation; however, the neurodevelopmental mechanisms by whichSLC35A2disruption leads to clinical and histopathological features remain unspecified. We hypothesized that focal knockout (KO) or knockdown (KD) ofSlc35a2in the developing mouse cortex would disrupt cerebral cortical development through altered neuronal migration and cause changes in network excitability. We usedin uteroelectroporation (IUE) to introduce CRISPR/Cas9 and targeted guide RNAs or short-hairpin RNAs to achieveSlc35a2KO or KD, respectively, during early corticogenesis. FollowingSlc35a2KO or KD, we observed disrupted radial migration of transfected neurons evidenced by heterotopic cells located in lower cortical layers and in the sub-cortical white matter.Slc35a2KO in neurons did not induce changes in oligodendrocyte number, suggesting that the oligodendroglial hyperplasia observed in MOGHE originates from distinct cell autonomous effects. Spontaneous seizures were not observed, but intracranial EEG recordings after focal KO showed a reduced seizure threshold following pentylenetetrazol injection. These results demonstrate thatSlc35a2KO or KDin vivodisrupts corticogenesis through altered neuronal migration.