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bioRxiv · 10.1101/2024.02.18.580216

Slc35a2 mosaic knockout impacts cortical development, dendritic arborisation, and neuronal firing in the developing brain

Spyrou, J.·Aung, K. P.·Vanyai, H.·Leventer, R. J.·Maljevic, S.·Lockhart, P. J.·Howell, K. B.·Reid, C. A.
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Abstract

ObjectiveMild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is an important cause of drug-resistant epilepsy. A significant subset of individuals diagnosed with MOGHE display somatic mosaicism for loss-of-function variants in SLC35A2, which encodes the UDP-galactose transporter. We developed a mouse model to investigate the mechanism by which disruption of this transporter leads to a malformation of cortical development. MethodsWe used in utero electroporation and CRISPR/Cas9 to knockout Slc35a2 in a subset of layer 2/3 cortical neuronal progenitors in the developing brains of fetal mice to model mosaic expression. ResultsHistology of brain tissue in the mosaic Slc35a2 knockout mice revealed the presence of upper layer-derived cortical neurons in the white matter. In contrast, oligodendrocyte patterning was unchanged. Reconstruction of single filled neurons identified altered dendritic arborisation with Slc35a2 knockout neurons having increased complexity. Whole-cell electrophysiological recordings revealed that Slc35a2 knockout neurons display reduced action potential firing and increased afterhyperpolarisation duration compared with control neurons. Mosaic Slc35a2 knockout mice also exhibited significantly increased epileptiform spiking and increased locomotion. InterpretationWe successfully generated a mouse model of mosaic Slc35a2 deficiency, which recapitulates features of the human phenotype, including impaired neuronal migration. We show that knockout in layer 2/3 cortical neuron progenitors is sufficient to disrupt neuronal excitability and increase epileptiform activity and hyperactivity in mosaic mice. Our mouse model provides a unique opportunity to investigate the disease mechanism(s) that underpin MOGHE and facilitate the development of precision therapies.

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Spyrou, J., Aung, K. P., Vanyai, H., Leventer, R. J., Maljevic, S., Lockhart, P. J., Howell, K. B., Reid, C. A.. 2024-02-18. Slc35a2 mosaic knockout impacts cortical development, dendritic arborisation, and neuronal firing in the developing brain. https://doi.org/10.1101/2024.02.18.580216

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