WONOEP appraisal: Modeling early onset epilepsies

Abstract

Epilepsy has a peak incidence during the neonatal to early childhood period. These early onset epilepsies may be severe conditions frequently associated with comorbidities such as developmental deficits and intellectual disability and, in a significant percentage of patients, may be medication-resistant. The use of adult rodent models in the exploration of mechanisms and treatments for early life epilepsies is challenging, as it ignores significant age-specific developmental differences. More recently, models developed in immature animals, such as rodent pups, or in three-dimensional organoids may more closely model aspects of the immature brain and could result in more translatable findings. Although models are not perfect, they may offer a more controlled screening platform in studies of mechanisms and treatments, which cannot be done in pediatric patient cohorts. On the other hand, more simplified models with higher throughput capacities are required to deal with the large number of epilepsy candidate genes and the need for new treatment options. Therefore, a combination of different modeling approaches will be beneficial in addressing the unmet needs of pediatric epilepsy patients. In this review, we summarize the discussions on this topic that occurred during the XVI Workshop on Neurobiology of Epilepsy, organized in 2022 by the Neurobiology Commission of the International League Against Epilepsy. We provide an overview of selected models of early onset epilepsies, discussing their advantages and disadvantages. Heterologous expression models provide initial functional insights, and zebrafish, rodent models, and brain organoids present increasingly complex platforms for modeling and validating epilepsy-related phenomena. Together, these models offer valuable insights into early onset epilepsies and accelerate hypothesis generation and therapy discovery.

Keywords: acquired epilepsy; brain organoids; epilepsy syndromes; heterologous expression systems; rodents; zebrafish.

Figure 1:

Overview of epilepsy syndromes with onset (A) in neonates and infants (≤2 years) and in (B) childhood (2-12 years), based on the recent classification of epilepsy syndromes (adapted from (3,4,7) with permission). Not included in this figure are other significant epilepsy syndromes that start at variable ages, encompassing both individuals aged ≤18 years and those aged ≥19 years.

Figure 2:

A visual summary outlining the frequently utilized models for pediatric epilepsies, arranged from higher throughput to higher complexity, left to right. Heterologous expression models are shown in green, which may or may not include a human non-neuronal background depending on the cell types used. Blue represents 2D and 3D neuronal cultures, offering the advantage of incorporating a human neuronal background. Red corresponds to zebrafish and rodent models, which provide whole-organism platforms. Finally, in purple, the most complex model merges elements of both in vitro and in vivo models by implanting organoids within rodents.