Single-nucleus transcriptomics-based drug screening platform for focal cortical dysplasia.

Area of Science:

• Neuroscience
• Genomics
• Pharmacology

Background:

• Focal cortical dysplasias (FCDs) are a primary cause of drug-resistant epilepsy.
• The molecular complexity of FCDs hinders the development of effective antiseizure drugs.

Purpose of the Study:

• To investigate the transcriptional landscape of human FCDs.
• To identify potential therapeutic targets and compounds for treating refractory epilepsy.

Main Methods:

• Single-nucleus RNA sequencing was performed on 49 human neocortical specimens (FCD I-III).
• Transcriptional signatures were integrated with the Connectivity Map to prioritize drug candidates.
• In vivo efficacy of candidate compounds was assessed in epilepsy models.

Main Results:

• Significant transcriptional alterations were observed in non-neuronal cells (astrocytes, vascular cells), indicating dysfunction.
• Vascular-associated signatures were a common feature across FCD subtypes.
• Four compounds (Betamethasone, Lodamin, Valproxam, Licochalcone A) demonstrated reduced seizure-like activity in vivo.

Conclusions:

• A multicellular, transcriptome-guided framework can link disease signatures to therapeutic strategies for refractory epilepsy.
• The study highlights vascular cell dysfunction as a convergent feature in FCDs.
• Identified compounds offer potential avenues for novel antiseizure medication development.