Slc35a2 mosaic knockout impacts cortical development, dendritic arborisation, and neuronal firing

Area of Science:

• Neuroscience
• Genetics
• Epilepsy Research

Background:

• Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is a significant cause of drug-resistant epilepsy.
• Somatic mosaicism for loss-of-function variants in SLC35A2, encoding the UDP-galactose transporter, is found in a subset of MOGHE patients.

Purpose of the Study:

• To develop and characterize a mouse model for MOGHE by investigating the effects of disrupted SLC35A2 function on cortical development.
• To understand how mosaic disruption of the UDP-galactose transporter leads to malformations and epilepsy.

Main Methods:

• Utilized in utero electroporation and CRISPR/Cas9 to create mosaic Slc35a2 knockout in layer 2/3 cortical neuronal progenitors in mice.
• Verified mosaicism using next-generation sequencing and immunohistochemistry.
• Analyzed neuronal migration, dendritic complexity, electrophysiology, and behavioral phenotypes.

Main Results:

• Mosaic Slc35a2 knockout mice exhibited misplaced cortical neurons in the white matter.
• Knockout neurons showed altered dendritic arborization and reduced action potential firing.
• Mosaic mice displayed increased epileptiform spiking and hyperactivity.

Conclusions:

• The developed mouse model successfully recapitulates key features of human MOGHE, including impaired neuronal migration.
• Mosaic Slc35a2 deficiency in cortical progenitors disrupts neuronal excitability and leads to epilepsy-related phenotypes.
• This model serves as a valuable tool for studying MOGHE pathogenesis and developing targeted therapies.