Abstracts

Rationale: Brain somatic variants in SLC35A2 have been identified as a genetic marker for mild malformations of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) (Bonduelle et al., Najm et al, Winawer et al). The role of SLC35A2 in cortical development, as well as the contributions of abnormal neurons and oligodendrocytes to seizure activity in MOGHE, remain largely unexplored. In this study, we generated two Slc35a2 conditional knockout mouse lines to investigate cell type-specific roles of SLC35A2 in cortical development and its contributions to epilepsy. Given that loss-of-function somatic variants in SLC35A2 have been identified in MOGHE patients, understanding how knockout affects neurons and oligodendrocytes, and their contribution to seizure activity, could provide critical insights into the disease mechanisms and potential therapeutic targets.

Methods: To investigate the role of SLC35A2 in cortical development and epilepsy, we generated a mouse model with a floxed Slc35a2 allele and crossed it with Emx1-Cre or Olig2-Cre to induce Cre-mediated recombination in forebrain neurons and glia, or in oligodendrocytes, respectively (Gorski et al., Dimou et al). We evaluated these models through behavioral tests for anxiety and social behavior, developmental milestone assessments, histological examinations of cortical development, and EEG recordings for seizure activity.


Results: Emx1-Cre-mediated Slc35a2 knockout mice exhibited significant cortical development abnormalities, early-onset seizures, and developmental delays, mirroring MOGHE patient phenotypes. These mice also showed early lethality and impaired radial neuronal migration and abnormal cortical layering. In contrast, Olig2-Cre-mediated Slc35a2 knockout mice displayed a milder phenotype with improved survival but still demonstrated abnormal EEG activity.

Conclusions: This study highlights the essential role of SLC35A2 in cortical development and its involvement in epilepsy within the context of MOGHE. The distinct phenotypes of the Emx1-Cre-mediated and Olig2-Cre-mediated conditional knockout mouse models underscore the significant contributions of both neurons and oligodendrocytes to the pathology of MOGHE. These findings provide a deeper understanding of the disease mechanisms and underscore the importance of SLC35A2 in brain development and function. Insights gained from this research could guide the development of targeted therapeutic strategies for MOGHE and related disorders.


Funding: Funding by NIH-NINDS (R01NS094596) to P.C. and NIH-NINDS (R01NS129784) to TAB.