Dysregulated Notch1 signaling in seizures: Insights from a genetic model of absence epilepsy

The Notch signaling pathway is integral to the development, maintenance, and function of the CNS by regulating neural stem cell fate, neurogenesis, and glial activity. Notch1, a key receptor in this pathway, is essential not only for synaptic plasticity but also for maintaining proper neuron-glia interactions. Dysregulation of Notch signaling has been implicated in various neurological disorders. However, the role of this pathway in absence epilepsy requires further elucidation.

Here, we used a combination of bioinformatics, molecular, and histological analyses to investigate the expression patterns and correlations among Notch1, its regulators (NLE1 and Jagged1), and cellular markers GFAP and NeuN in human datasets and the WAG/Rij rat strain, a commonly used experimental model for absence seizures.

Our findings revealed region-specific expression correlations in healthy human brain tissue and age-related expression changes in WAG/Rij and Wistar rat strains. Furthermore, WAG/Rij rats showed significant changes in the expression of Notch1, NLE1, Jagged1, GFAP, and NeuN compared to Wistar rat controls, with altered gene correlations suggesting disrupted Notch signaling. Moreover, significant alterations in the neuron-glial ratio, along with changes in the immunohistological expression patterns of these markers, were observed.

These findings suggest that impaired Notch pathway dynamics may play a role in the pathophysiology of absence seizures and point to potential molecular mechanisms for future therapeutic investigation.