Focal cortical dysplasias: modeling pediatric drug-resistant epilepsy using human brain organoids

Epilepsy is a prevalent neurological disorder characterized by recurrent, unprovoked seizures and altered electroencephalographic patterns. This condition is viewed as a malfunctioning of extensive neural networks due to an imbalance of excitatory and inhibitory signals leading neurons to be excessively excitable and to abnormal synchronized electrical activity. Despite the growing number of new antiepileptic drugs, patients suffering from drug-resistant forms of epilepsy do not respond to pharmacological treatment, and the only effective cure remains the neurosurgical resection of the epileptic focus. Nevertheless, several patients fail to achieve seizure freedom after surgical resection. This emphasizes the urgent need for novel human-relevant models to explore the mechanisms underlying drug-refractory forms of epilepsy. While acute and organotypic slices from resected neurological tissue offer a promising method for studying patient-derived brain tissue mechanisms, this technique is limited by its inherently low throughput and challenges in obtaining appropriate control tissue. Recent advances in organoid technology have allowed for the generation of cerebral dorsal/ventral assembloids, which more accurately model the functional connectivity between excitatory and inhibitory neurons and recapitulate key aspects of cortical circuits. This review summarizes current knowledge on the use of human brain organoids and assembloids to model epilepsy, with a particular focus on organoids harboring focal cortical dysplasia-linked mutations. Human brain organoids and assembloids will allow addressing an important question in the field, namely the relative contribution of neurodevelopmental defects vs. those arising at later stages of CNS development. Limitations of this "neuron-only" <i>in vitro</i> model and potential ways to include non-neuronal cells will also be discussed. Finally, we highlight recent advances in employing these new powerful platforms for investigating network dysfunctions underlying FCDs, screening potential antiepileptic drug candidates, and developing personalized therapeutic strategies.